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Marjot T, Webb GJ, Barritt AS, et al. COVID-19 and liver disease: mechanistic and clinical perspectives. Nat Rev Gastroenterol Hepatol. 2021;18(5):348-364doi: 10.1038/s41575-021-00426-4.
Marjot, T., Webb, G. J., Barritt, A. S., Moon, A. M., Stamataki, Z., Wong, V. W., & Barnes, E. (2021). COVID-19 and liver disease: mechanistic and clinical perspectives. Nature reviews. Gastroenterology & hepatology, 18(5), 348-364. https://doi.org/10.1038/s41575-021-00426-4
Marjot, Thomas, et al. "COVID-19 and liver disease: mechanistic and clinical perspectives." Nature reviews. Gastroenterology & hepatology vol. 18,5 (2021): 348-364. doi: https://doi.org/10.1038/s41575-021-00426-4
Marjot T, Webb GJ, Barritt AS, Moon AM, Stamataki Z, Wong VW, Barnes E. COVID-19 and liver disease: mechanistic and clinical perspectives. Nat Rev Gastroenterol Hepatol. 2021 May;18(5):348-364. doi: 10.1038/s41575-021-00426-4. Epub 2021 Mar 10. PMID: 33692570; PMCID: PMC7945972.
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Nat Rev Gastroenterol Hepatol. 2021 May;18(5):348-364. doi: 10.1038/s41575-021-00426-4. Epub 2021 Mar 10.

COVID-19 and liver disease: mechanistic and clinical perspectives.

Nature reviews. Gastroenterology & hepatology

Thomas Marjot, Gwilym J Webb, Alfred S Barritt, Andrew M Moon, Zania Stamataki, Vincent W Wong, Eleanor Barnes

Affiliations

  1. Oxford Liver Unit, Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, UK. [email protected].
  2. Cambridge Liver Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK.
  3. Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA.
  4. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
  5. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
  6. Oxford Liver Unit, Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, UK. [email protected].

PMID: 33692570 PMCID: PMC7945972 DOI: 10.1038/s41575-021-00426-4

Abstract

Our understanding of the hepatic consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its resultant coronavirus disease 2019 (COVID-19) has evolved rapidly since the onset of the pandemic. In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury. Furthermore, large international cohorts have been able to characterize the disease course of COVID-19 in patients with pre-existing chronic liver disease. Patients with cirrhosis have particularly high rates of hepatic decompensation and death following SARS-CoV-2 infection and we outline hypotheses to explain these findings, including the possible role of cirrhosis-associated immune dysfunction. This finding contrasts with outcome data in pharmacologically immunosuppressed patients after liver transplantation who seem to have comparatively better outcomes from COVID-19 than those with advanced liver disease. Finally, we discuss the approach to SARS-CoV-2 vaccination in patients with cirrhosis and after liver transplantation and predict how changes in social behaviours and clinical care pathways during the pandemic might lead to increased liver disease incidence and severity.

References

  1. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) https://coronavirus.jhu.edu/map.html (2021). - PubMed
  2. Berlin, D. A., Gulick, R. M. & Martinez, F. J. Severe Covid-19. N. Engl. J. Med. 383, 2451–2460 (2020). - PubMed
  3. Tay, M. Z., Poh, C. M., Renia, L., MacAry, P. A. & Ng, L. F. P. The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 20, 363–374 (2020). - PubMed
  4. World Health Organization. Clinical Management of COVID-19: Interim Guidance (2020). - PubMed
  5. Williamson, E. J. et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 584, 430–436 (2020). - PubMed
  6. Ioannou, G. N. et al. Risk factors for hospitalization, mechanical ventilation, or death among 10131 US veterans with SARS-CoV-2 infection. JAMA Netw. Open 3, e2022310 (2020). - PubMed
  7. Group, R. C. et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2021436 (2020). - PubMed
  8. Wiersinga, W. J., Rhodes, A., Cheng, A. C., Peacock, S. J. & Prescott, H. C. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 324, 782–793 (2020). - PubMed
  9. Albillos, A., Lario, M. & Álvarez-Mon, M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J. Hepatol. 61, 1385–1396 (2014). - PubMed
  10. Tapper, E. B., Robson, S. C. & Malik, R. Coagulopathy in cirrhosis - the role of the platelet in hemostasis. J. Hepatol. 59, 889–890 (2013). - PubMed
  11. Collaborators, G. B. D. C. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol. 5, 245–266 (2020). - PubMed
  12. Pirola, C. J. & Sookoian, S. SARS-CoV-2 virus and liver expression of host receptors: putative mechanisms of liver involvement in COVID-19. Liver Int. 40, 2038–2040 (2020). Gene expression profiles in human liver showing ACE2 receptors present on cholangiocytes and hepatocytes. - PubMed
  13. Qi, F., Qian, S., Zhang, S. & Zhang, Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem. Biophys. Res. Commun. 526, 135–140 (2020). - PubMed
  14. De Smet, V., Verhulst, S. & van Grunsven, L. A. Single cell RNA sequencing analysis did not predict hepatocyte infection by SARS-CoV-2. J. Hepatol. 73, 993–995 (2020). - PubMed
  15. Chu, H. et al. Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study. Lancet Microbe 1, e14–e23 (2020). - PubMed
  16. Ma-Lauer, Y. et al. p53 down-regulates SARS coronavirus replication and is targeted by the SARS-unique domain and PLpro via E3 ubiquitin ligase RCHY1. Proc. Natl Acad. Sci. USA 113, E5192–E5201 (2016). - PubMed
  17. Zhao, B. et al. Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids. Protein Cell 11, 771–775 (2020). ACE2 and TMPRSS2 expression on liver ductal organoids permitting SARS-CoV-2 infection. - PubMed
  18. Gaebler, C. et al. Evolution of antibody immunity to SARS-CoV-2. Nature https://doi.org/10.1038/s41586-021-03207-w (2021). - PubMed
  19. Yang, L. et al. A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell 27, 125–136.e7 (2020). - PubMed
  20. Paizis, G. et al. Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut 54, 1790–1796 (2005). Study in pre-COVID-19 era demonstrating upregulated hepatic ACE2 expression patients with cirrhosis. - PubMed
  21. Fondevila, M. F. et al. Obese patients with NASH have increased hepatic expression of SARS-CoV-2 critical entry points. J. Hepatol. 74, 469–471 (2021). - PubMed
  22. Herath, C. B. et al. Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis. J. Hepatol. 47, 387–395 (2007). - PubMed
  23. Chua, R. L. et al. COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat. Biotechnol. 38, 970–979 (2020). - PubMed
  24. Ziegler, C. G. K. et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 181, 1016–1035.e19 (2020). - PubMed
  25. Onabajo, O. O. et al. Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor. Nat. Genet. 52, 1283–1293 (2020). - PubMed
  26. Wei, C. et al. HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Nat. Metab. 2, 1391–1400 (2020). - PubMed
  27. Grove, J. et al. Scavenger receptor BI and BII expression levels modulate hepatitis C virus infectivity. J. Virol. 81, 3162–3169 (2007). - PubMed
  28. Zuo, T. et al. Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut 70, 276–284 (2021). - PubMed
  29. Lamers, M. M. et al. SARS-CoV-2 productively infects human gut enterocytes. Science 369, 50–54 (2020). - PubMed
  30. Qian, Q. et al. Direct evidence of active SARS-CoV-2 replication in the intestine. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa925 (2020). - PubMed
  31. Sonzogni, A. et al. Liver histopathology in severe COVID 19 respiratory failure is suggestive of vascular alterations. Liver Int. 40, 2110–2116 (2020). Liver histology from 48 patients who died from COVID-19 respiratory failure showing high rates of steatosis and microthrombotic disease. SARS-CoV-2 was detected in liver tissue in 68% of patients. - PubMed
  32. Wang, Y. et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J. Hepatol. 73, 807–816 (2020). - PubMed
  33. Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020). - PubMed
  34. Nie, X. et al. Multi-organ proteomic landscape of COVID-19 autopsies. Cell 184, 775–791.e14 (2021). In this study, 11,394 proteins were quantified in autopsy samples from 7 organs in 19 patients with COVID-19. Widespread dysregulation of liver proteins was detected in associated with multiorgan dysfunction and histological damage. - PubMed
  35. Guan, W. J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720 (2020). - PubMed
  36. Sultan, S. et al. AGA institute rapid review of the gastrointestinal and liver manifestations of COVID-19, meta-analysis of international data, and recommendations for the consultative management of patients with COVID-19. Gastroenterology 159, 320–334.e27 (2020). - PubMed
  37. Richardson, S. et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area. JAMA 323, 2052–2059 (2020). - PubMed
  38. Goyal, P. et al. Clinical characteristics of Covid-19 in New York city. N. Engl. J. Med. 382, 2372–2374 (2020). - PubMed
  39. Youssef, M. et al. COVID-19 and liver dysfunction: a systematic review and meta-analysis of retrospective studies. J. Med. Virol. 92, 1825–1833 (2020). - PubMed
  40. Hundt, M. A., Deng, Y., Ciarleglio, M. M., Nathanson, M. H. & Lim, J. K. Abnormal liver tests in COVID-19: a retrospective observational cohort study of 1827 patients in a major US Hospital Network. Hepatology 72, 1169–1176 (2020). - PubMed
  41. Elmunzer, B. J. et al. Digestive manifestations in patients hospitalized with COVID-19. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2020.09.041 (2020). - PubMed
  42. Fu, Y. et al. Clinical features of COVID-19-infected patients with elevated liver biochemistries: a multicenter, retrospective study. Hepatology https://doi.org/10.1002/hep.31446 (2020). - PubMed
  43. Mao, R. et al. Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 5, 667–678 (2020). - PubMed
  44. Phipps, M. M. et al. Acute liver injury in COVID-19: prevalence and association with clinical outcomes in a large US cohort. Hepatology 72, 807–817 (2020). Large retrospective cohort study in USA (n = 3,381) demonstrating that acute liver injury is common and often mild during COVID-19. Poor outcomes were associated with severe liver injury. - PubMed
  45. Zhou, F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062 (2020). Retrospective cohort study performed in China providing early data on the clinical course and laboratory parameters, including liver enzymes, among patients with COVID-19. - PubMed
  46. Singh, S. & Khan, A. Clinical characteristics and outcomes of coronavirus disease 2019 among patients with preexisting liver disease in the united states: a multicenter research network study. Gastroenterology 159, 768–771.e3 (2020). - PubMed
  47. Xu, Z. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 8, 420–422 (2020). - PubMed
  48. Lagana, S. M. et al. Hepatic pathology in patients dying of COVID-19: a series of 40 cases including clinical, histologic, and virologic data. Mod. Pathol. 33, 2147–2155 (2020). - PubMed
  49. Jothimani, D., Venugopal, R., Abedin, M. F., Kaliamoorthy, I. & Rela, M. COVID-19 and the liver. J. Hepatol. 73, 1231–1240 (2020). - PubMed
  50. Bloom, P. P. et al. Liver biochemistries in hospitalized patients with COVID-19. Hepatology https://doi.org/10.1002/hep.31326 (2020). - PubMed
  51. Buckholz, A. P., Kaplan, A., Rosenblatt, R. E. & Wan, D. Clinical characteristics, diagnosis, and outcomes of 6 patients with COVID-19 infection and rhabdomyolysis. Mayo Clin. Proc. 95, 2557–2559 (2020). - PubMed
  52. Zhang, Y. et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N. Engl. J. Med. 382, e38 (2020). - PubMed
  53. Díaz, L. A. et al. High prevalence of hepatic steatosis and vascular thrombosis in COVID-19: a systematic review and meta-analysis of autopsy data. World J. Gastroenterol. 26, 7693–7706 (2020) - PubMed
  54. Papic, N. et al. Liver involvement during influenza infection: perspective on the 2009 influenza pandemic. Influenza Other Respir. Viruses 6, e2–e5 (2012). - PubMed
  55. Mehta, P. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395, 1033–1034 (2020). - PubMed
  56. Da, B. L. et al. Liver injury in hospitalized patients with COVID-19 correlates with hyper inflammatory response and elevated IL-6. Hepatol. Commun. 5, 177–188 (2020). - PubMed
  57. Liu, J. et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 55, 102763 (2020). - PubMed
  58. Diao, B. et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front. Immunol. 11, 827 (2020). - PubMed
  59. Al-Samkari, H. et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 136, 489–500 (2020). - PubMed
  60. Klok, F. A. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb. Res. 191, 148–150 (2020). - PubMed
  61. Middeldorp, S. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J. Thromb. Haemost. 18, 1995–2002 (2020). - PubMed
  62. Poissy, J. et al. Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation 142, 184–186 (2020). - PubMed
  63. Olry, A. et al. Drug-induced liver injury and COVID-19 infection: the rules remain the same. Drug Saf. 43, 615–617 (2020). - PubMed
  64. Cao, B. et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N. Engl. J. Med. 382, 1787–1799 (2020). - PubMed
  65. Cai, Q. et al. COVID-19: abnormal liver function tests. J. Hepatol. 73, 566–574 (2020). - PubMed
  66. Muhovic, D. et al. First case of drug-induced liver injury associated with the use of tocilizumab in a patient with COVID-19. Liver Int. 40, 1901–1905 (2020). - PubMed
  67. Mahamid, M., Mader, R. & Safadi, R. Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions. Clin. Pharmacol. 3, 39–43 (2011). - PubMed
  68. Beigel, J. H. et al. Remdesivir for the treatment of Covid-19 - final report. N. Engl. J. Med. 383, 1813–1826 (2020). - PubMed
  69. Montastruc, F., Thuriot, S. & Durrieu, G. Hepatic disorders with the use of remdesivir for coronavirus 2019. Clin. Gastroenterol. Hepatol. 18, 2835–2836 (2020). - PubMed
  70. WHO Solidarity Trial Consortium. et al. Repurposed antiviral drugs for Covid-19 - Interim WHO Solidarity Trial Results. N. Engl. J. Med. 384, 497–511 (2021). - PubMed
  71. Ponziani, F. R. et al. Liver involvement is not associated with mortality: results from a large cohort of SARS-CoV-2 positive patients. Aliment. Pharmacol. Ther. 52, 1060–1068 (2020). - PubMed
  72. Yip, T. C. F. et al. Liver injury is independently associated with adverse clinical outcomes in patients with COVID-19. Gut https://doi.org/10.1136/gutjnl-2020-321726 (2020). - PubMed
  73. Weber, S. et al. Liver function test abnormalities at hospital admission are associated with severe course of SARS-CoV-2 infection: a prospective cohort study. Gut https://doi.org/10.1136/gutjnl-2020-323800 (2021). - PubMed
  74. Ding, Z. Y. et al. Association of liver abnormalities with in-hospital mortality in patients with COVID-19. J. Hepatol. https://doi.org/10.1016/j.jhep.2020.12.012 (2020). - PubMed
  75. Zhang, Y. et al. Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single centre in Wuhan city, China. Liver Int. 40, 2095–2103 (2020). - PubMed
  76. Yadav, D. K. et al. Involvement of liver in COVID-19: systematic review and meta-analysis. Gut https://doi.org/10.1136/gutjnl-2020-322072 (2020). - PubMed
  77. Lei, F. et al. Longitudinal association between markers of liver injury and mortality in COVID-19 in China. Hepatology 72, 389–398 (2020). Multicentre retrospective cohort study of 5,771 patients hospitalized with COVID-19 in China describing longitudinal patterns in liver biochemistry. - PubMed
  78. Bangash, M. N. et al. SARS-CoV-2: is the liver merely a bystander to severe disease? J. Hepatol. 73, 995–996 (2020). - PubMed
  79. Noor, M. T. & Manoria, P. Immune dysfunction in cirrhosis. J. Clin. Transl. Hepatol. 5, 50–58 (2017). - PubMed
  80. Pose, E. et al. PD-L1 is overexpressed in liver macrophages in chronic liver diseases and its blockade improves the antibacterial activity against infections. Hepatology https://doi.org/10.1002/hep.31644 (2020). - PubMed
  81. Piano, S., Brocca, A., Mareso, S. & Angeli, P. Infections complicating cirrhosis. Liver Int. 38 (Suppl. 1), 126–133 (2018). - PubMed
  82. Fan, V. S. et al. Risk factors for testing positive for SARS-CoV-2 in a national US healthcare system. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa1624 (2020). - PubMed
  83. Ioannou, G. N. et al. Cirrhosis and SARS-CoV-2 infection in US veterans: risk of infection, hospitalization, ventilation and mortality. Hepatology https://doi.org/10.1002/hep.31649 (2020). United States data from electronic health records showing a lower risk of positive SARS-CoV-2 testing but higher rates of mortality from COVID-19 in patients with cirrhosis compared to those without. - PubMed
  84. Fine, M. J. et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N. Engl. J. Med. 336, 243–250 (1997). - PubMed
  85. Schütte, A., Ciesek, S., Wedemeyer, H. & Lange, C. M. Influenza virus infection as precipitating event of acute-on-chronic liver failure. J. Hepatol. 70, 797–799 (2019). - PubMed
  86. Eslam, M. et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J. Hepatol. 73, 202–209 (2020). - PubMed
  87. Ji, D. et al. Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study. J. Hepatol. 73, 451–453 (2020). - PubMed
  88. Zhou, Y. J. et al. Younger patients with MAFLD are at increased risk of severe COVID-19 illness: a multicenter preliminary analysis. J. Hepatol. 73, 719–721 (2020). - PubMed
  89. Roca-Fernandez, A. et al. High liver fat associates with higher risk of developing symptomatic covid-19 infection - initial UK biobank observations. medRxiv https://doi.org/10.1101/2020.06.04.20122457 (2020). - PubMed
  90. Lopez-Mendez, I. et al. Association of liver steatosis and fibrosis with clinical outcomes in patients with SARS-CoV-2 infection (COVID-19). Ann. Hepatol. 20, 100271 (2021). - PubMed
  91. Marjot, T. et al. Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study. J. Hepatol. 74, 567–577 (2020). - PubMed
  92. Marjot, T. et al. SARS-CoV-2 infection in patients with autoimmune hepatitis. J. Hepatol. https://doi.org/10.1016/j.jhep.2021.01.021 (2021). Largest cohort of patients with AIH and SARS-CoV-2 infection (n = 70) showing equivalent risk of death compared to propensity score-matched patients with other aetiology of liver disease (n = 862) and patients without liver disease (n = 769). - PubMed
  93. Iavarone, M. et al. High rates of 30-day mortality in patients with cirrhosis and COVID-19. J. Hepatol. 73, 1063–1071 (2020). Multicentre study in northern Italy reporting outcomes and management of patients with cirrhosis and COVID-19, including the use of thromboprophylaxis. - PubMed
  94. Bajaj, J. S. et al. Cirrhosis is associated with high mortality and readmissions over 90 days regardless of COVID-19: a multi-center cohort. Liver Transpl. https://doi.org/10.1002/lt.25981 (2021). Longitudinal follow-up of patients with cirrhosis who survived the acute COVID-19 episode showing equivalent mortality at 90-days compared to those with cirrhosis alone. - PubMed
  95. Wu, T. et al. Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure. Gut 67, 2181–2191 (2018). - PubMed
  96. Moreau, R. et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 144, 1426–1437.e9 (2013). - PubMed
  97. Horwitz, L. I. et al. Trends in COVID-19 risk-adjusted mortality rates. J. Hosp. Med. 16, 90–92 (2021). - PubMed
  98. Duddempudi, A. T. Immunology in alcoholic liver disease. Clin. Liver Dis. 16, 687–698 (2012). - PubMed
  99. Yeoh, Y. K. et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut https://doi.org/10.1136/gutjnl-2020-323020 (2021). - PubMed
  100. Bajaj, J. S. Altered microbiota in cirrhosis and its relationship to the development of infection. Clin. Liver Dis. 14, 107–111 (2019). - PubMed
  101. Adeniji, N. et al. Socioeconomic factors contribute to the higher risk of COVID-19 in racial and ethnic minorities with chronic liver diseases (CLD). Gastroenterology https://doi.org/10.1053/j.gastro.2020.11.035 (2020). - PubMed
  102. Wegermann, K. et al. Racial and socioeconomic disparities in utilization of telehealth in patients with liver disease during COVID-19. Dig. Dis. Sci. https://doi.org/10.1007/s10620-021-06842-5 (2021). - PubMed
  103. Boettler, T. et al. Impact of COVID-19 on the care of patients with liver disease: EASL-ESCMID position paper after 6 months of the pandemic. JHEP Rep. 2, 100169 (2020). This article discusses the impact of COVID-19 on hepatology care and provides updates on the recommended practice for clinicians taking care of patients with liver diseases. - PubMed
  104. Fix, O. K. et al. Clinical best practice advice for hepatology and liver transplant providers during the COVID-19 pandemic: AASLD expert panel consensus statement. Hepatology 72, 287–304 (2020). AASLD guidance on the management of patients with liver disease and liver transplant recipients during the COVID-19 pandemic. - PubMed
  105. APASL Covid-19 Task Force, Lau, G. & Sharma, M. Clinical practice guidance for hepatology and liver transplant providers during the COVID-19 pandemic: APASL expert panel consensus recommendations. Hepatol. Int. 14, 415–428 (2020). - PubMed
  106. Angeli, P. et al. EASL clinical practice guidelines for the management of patients with decompensated cirrhosis. J. Hepatol. 69, 406–460 (2018). - PubMed
  107. Manolis, A. S., Manolis, T. A., Manolis, A. A., Papatheou, D. & Melita, H. COVID-19 infection: viral macro- and micro-vascular coagulopathy and thromboembolism/prophylactic and therapeutic management. J. Cardiovasc. Pharmacol. Ther. 26, 12–24 (2021). - PubMed
  108. Bikdeli, B. et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J. Am. Coll. Cardiol. 75, 2950–2973 (2020). - PubMed
  109. Turco, L., de Raucourt, E., Valla, D. C. & Villa, E. Anticoagulation in the cirrhotic patient. JHEP Reports 1, 227–239 (2019). - PubMed
  110. Loffredo, L., Pastori, D., Farcomeni, A. & Violi, F. Effects of anticoagulants in patients with cirrhosis and portal vein thrombosis: a systematic review and meta-analysis. Gastroenterology 153, 480–487.e1 (2017). - PubMed
  111. Tritschler, T. et al. Anticoagulant interventions in hospitalized patients with COVID-19: a scoping review of randomized controlled trials and call for international collaboration. J. Thromb. Haemost. 18, 2958–2967 (2020). - PubMed
  112. Lemos, A. C. B. et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID). Thromb. Res. 196, 359–366 (2020). - PubMed
  113. Watt, K. D. Keys to long-term care of the liver transplant recipient. Nat. Rev. Gastroenterol. Hepatol. 12, 639–648 (2015). - PubMed
  114. Benitez, C. et al. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology 58, 1824–1835 (2013). - PubMed
  115. Colmenero, J. et al. Epidemiological pattern, incidence and outcomes of COVID-19 in liver transplant patients. J. Hepatol. 74, 148–155 (2021). Prospective nationwide study including a consecutive cohort of liver transplant patients with COVID-19 in Spain. Mortality rates in LT recipients were lower than those observed in the matched general population. - PubMed
  116. Ravanan, R. et al. SARS-CoV-2 infection and early mortality of wait-listed and solid organ transplant recipients in England: a national cohort study. Am. J. Transplant. 20, 3008–3018 (2020). - PubMed
  117. Webb, G. J. et al. Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study. Lancet Gastroenterol. Hepatol. 5, 1008–1016 (2020). International registry data for 151 LT recipients and 627 non-transplant patients showing equivalent risk of mortality following SARS-CoV-2 infection in propensity score-matched analysis. - PubMed
  118. Rauber, C. et al. SARS-CoV-2 seroprevalence and clinical features of COVID-19 in a German liver transplant recipient cohort: a prospective serosurvey study. Transplant. Proc. https://doi.org/10.1016/j.transproceed.2020.11.009 (2020). - PubMed
  119. Lee, B. T. et al. COVID-19 in liver transplant recipients: an initial experience from the US epicenter. Gastroenterology 159, 1176–1178.e2 (2020). - PubMed
  120. Pereira, M. R. et al. COVID-19 in solid organ transplant recipients: initial report from the US epicenter. Am. J. Transplant. 20, 1800–1808 (2020). - PubMed
  121. Mathur, A. K., Schaubel, D. E., Gong, Q., Guidinger, M. K. & Merion, R. M. Sex-based disparities in liver transplant rates in the United States. Am. J. Transplant. 11, 1435–1443 (2011). - PubMed
  122. Sharma, P. et al. Impact of MELD-based allocation on end-stage renal disease after liver transplantation. Am. J. Transplant. 11, 2372–2378 (2011). - PubMed
  123. Lieber, S. R. et al. The impact of post-transplant diabetes mellitus on liver transplant outcomes. Clin. Transplant. 33, e13554 (2019). - PubMed
  124. Everhart, J. E. et al. Weight change and obesity after liver transplantation: incidence and risk factors. Liver Transpl. Surg. 4, 285–296 (1998). - PubMed
  125. Su, F. et al. Aging of liver transplant registrants and recipients: trends and impact on waitlist outcomes, post-transplantation outcomes, and transplant-related survival benefit. Gastroenterology 150, 441–453.e6 (2016). - PubMed
  126. Seyam, M., Neuberger, J. M., Gunson, B. K. & Hubscher, S. G. Cirrhosis after orthotopic liver transplantation in the absence of primary disease recurrence. Liver Transpl. 13, 966–974 (2007). - PubMed
  127. Rabiee, A. et al. Liver injury in liver transplant recipients with coronavirus disease 2019 (COVID-19): US multicenter experience. Hepatology https://doi.org/10.1002/hep.31574 (2020). - PubMed
  128. Clift, A. K. et al. Living risk prediction algorithm (QCOVID) for risk of hospital admission and mortality from coronavirus 19 in adults: national derivation and validation cohort study. BMJ 371, m3731 (2020). - PubMed
  129. Webb, G. J., Moon, A. M., Barnes, E., Barritt, A. S. 4th & Marjot, T. Age and comorbidity are central to the risk of death from COVID-19 in liver transplant recipients. J. Hepatol. https://doi.org/10.1016/j.jhep.2021.01.036 (2021). - PubMed
  130. Del Valle, D. M. et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 26, 1636–1643 (2020). - PubMed
  131. Zhang, Q. et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science https://doi.org/10.1126/science.abd4570 (2020). - PubMed
  132. Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science https://doi.org/10.1126/science.abd4585 (2020). - PubMed
  133. RECOVERY Collaborative Group. et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2021436 (2020). - PubMed
  134. D’Antiga, L. Coronaviruses and immunosuppressed patients: the facts during the third epidemic. Liver Transpl. 26, 832–834 (2020). - PubMed
  135. Boettler, T. et al. Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper. JHEP Rep. 2, 100113 (2020). - PubMed
  136. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). - PubMed
  137. Voysey, M. et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 397, 99–111 (2021). - PubMed
  138. Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). - PubMed
  139. Logunov, D. Y. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet https://doi.org/10.1016/S0140-6736(21)00234-8 (2021). - PubMed
  140. Marjot, T. et al. SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question. Lancet Gastroenterol. Hepatol. (2021). Summary of SARS-CoV-2 vaccination safety and efficacy data from phase III trials and discussion of key clinical and research considerations for patients with liver disease and transplantation. - PubMed
  141. Lebosse, F. et al. CD8 - PubMed
  142. Liaskou, E. & Hirschfield, G. M. Cirrhosis-associated immune dysfunction: novel insights in impaired adaptive immunity. EBioMedicine 50, 3–4 (2019). - PubMed
  143. Arvaniti, V. et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 139, 1246–1256 (2010). - PubMed
  144. McCashland, T. M., Preheim, L. C. & Gentry, M. J. Pneumococcal vaccine response in cirrhosis and liver transplantation. J. Infect. Dis. 181, 757–760 (2000). - PubMed
  145. Aggeletopoulou, I., Davoulou, P., Konstantakis, C., Thomopoulos, K. & Triantos, C. Response to hepatitis B vaccination in patients with liver cirrhosis. Rev. Med. Virol. 27, https://doi.org/10.1002/rmv.1942 (2017). - PubMed
  146. Chong, P. P. & Avery, R. K. A comprehensive review of immunization practices in solid organ transplant and hematopoietic stem cell transplant recipients. Clin. Ther. 39, 1581–1598 (2017). - PubMed
  147. Fix, O. K. AASLD expert panel consensus statement: vaccines to prevent COVID-19 infection in patients with liver disease. (AASLD, 2021). AASLD consensus statements on the approach to SARS-CoV-2 vaccination in patients with liver disease and after transplantation. - PubMed
  148. Tapper, E. B. & Asrani, S. K. The COVID-19 pandemic will have a long-lasting impact on the quality of cirrhosis care. J. Hepatol. 73, 441–445 (2020). - PubMed
  149. Garcia-Tsao, G., Abraldes, J. G., Berzigotti, A. & Bosch, J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 65, 310–335 (2017). - PubMed
  150. Erman, A., Wong, W. W. L., Feld, J. J., Grootendorst, P. & Krahn, M. D. The health impact of delaying direct-acting antiviral treatment for chronic hepatitis C: a decision-analytic approach. Liver Int. 40, 51–59 (2020). - PubMed
  151. Wu, C. Y. et al. Association between ultrasonography screening and mortality in patients with hepatocellular carcinoma: a nationwide cohort study. Gut 65, 693–701 (2016). - PubMed
  152. Amaddeo, G. et al. Impact of COVID-19 on the management of hepatocellular carcinoma in a high-prevalence area. JHEP Rep. 3, 100199 (2021). Multicentre retrospective study in France showing longer durations to HCC treatment during the pandemic than during the same time period the preceding year. - PubMed
  153. Di Maira, T. & Berenguer, M. COVID-19 and liver transplantation. Nat. Rev. Gastroenterol. Hepatol. 17, 526–528 (2020). - PubMed
  154. Merola, J., Schilsky, M. L. & Mulligan, D. C. The impact of COVID-19 on organ donation, procurement and liver transplantation in the United States. Hepatol. Commun. 5, 5–11 (2020). - PubMed
  155. Ritschl, P. V. et al. Solid organ transplantation programs facing lack of empiric evidence in the COVID-19 pandemic: a by-proxy society recommendation consensus approach. Am. J. Transplant. 20, 1826–1836 (2020). - PubMed
  156. Thorburn, D. et al. Resuming liver transplantation amid the COVID-19 pandemic. Lancet Gastroenterol. Hepatol. 6, 12–13 (2021). - PubMed
  157. World Health Organization. Global Hepatitis Report, 2017. https://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/ (2017). - PubMed
  158. Blach, S. et al. Impact of COVID-19 on global hepatitis C elimination efforts. J. Hepatol. 74, 31–36 (2021). - PubMed
  159. The Lancet Gastroenterology Hepatology. Eliminating viral hepatitis in the COVID-19 era: weighing challenge and opportunity. Lancet Gastroenterol. Hepatol. 5, 789 (2020). - PubMed
  160. Serper, M. et al. A local response to COVID-19 for advanced liver disease: current model of care, challenges and opportunities. J. Hepatol. 73, 708–709 (2020). - PubMed
  161. Verna, E. C. et al. Clinical research in hepatology in the COVID-19 pandemic and post-pandemic era: challenges and the need for innovation. Hepatology 72, 1819–1837 (2020). - PubMed
  162. Nicola, M. et al. The socio-economic implications of the coronavirus pandemic (COVID-19): a review. Int. J. Surg. 78, 185–193 (2020). - PubMed
  163. Nassisi, M. et al. Impact of the COVID-19 lockdown on basic science research in ophthalmology: the experience of a highly specialized research facility in France. Eye 34, 1187–1188 (2020). - PubMed
  164. The Grocer. Coronavirus: crisis drives £160 m additional spend on supermarket booze. (The Grocer, 2020). - PubMed
  165. Institute of Alcohol Studies. Alcohol consumption during the COVID-19 lockdown in the UK ias.org https://www.ias.org.uk/wp-content/uploads/2020/06/sb28062020.pdf (2020). - PubMed
  166. Public Health England. Wider impacts of COVID-19 on health monitoring tool. gov.uk https://www.gov.uk/government/publications/wider-impacts-of-covid-19-on-health-monitoring-tool (2020). - PubMed
  167. Institute of Alcohol Studies. Alcohol consumption during the COVID-19 pandemic in the UK – Second IAS briefing ias.org https://www.ias.org.uk/wp-content/uploads/2020/10/sb29102020.pdf (2020). - PubMed
  168. Da, B. L., Im, G. Y. & Schiano, T. D. COVID-19 hangover: a rising tide of alcohol use disorder and alcohol-associated liver disease. Hepatology 72, 1102–1108 (2020). - PubMed
  169. Niedzwiedz, C. L. et al. Mental health and health behaviours before and during the initial phase of the COVID-19 lockdown: longitudinal analyses of the UK Household Longitudinal Study. J. Epidemiol. Community Health 75, 224–231 (2021). Longitudinal questionnaire data in 9,748 UK adults showing an increase in regular and binge alcohol consumption during the early stages of the pandemic alongside reduced psychological wellbeing. - PubMed
  170. Winstock, A. R. et al. GDS COVID-19 Special Edition Key Findings Report https://www.globaldrugsurvey.com/gds-covid-19-special-edition-key-findings-report/ (2020). - PubMed
  171. Alcohol Toolkit Study. Alcohol Consumption in England ucl.ac.uk https://www.ucl.ac.uk/pals/research/clinical-educational-and-health-psychology/research-groups/health-psychology-research-45 (2020). - PubMed
  172. Kim, J. U. et al. Effect of COVID-19 lockdown on alcohol consumption in patients with pre-existing alcohol use disorder. Lancet Gastroenterol. Hepatol. 5, 886–887 (2020). - PubMed
  173. Cargill, Z. et al. Severe alcohol-related liver disease admissions post-COVID-19 lockdown: canary in the coal mine? Frontline Gastroenterol. https://doi.org/10.1136/flgastro-2020-101693 (2020). - PubMed
  174. Pellegrini, M. et al. Changes in weight and nutritional habits in adults with obesity during the “Lockdown” period caused by the COVID-19 virus emergency. Nutrients 12, 2016 (2020). - PubMed
  175. dQ&A. Impact of COVID-19 on the diabetes community in the United States https://d-qa.com/our-work/ (2020). - PubMed
  176. Mahmud, N., Hubbard, R. A., Kaplan, D. E. & Serper, M. Declining cirrhosis hospitalizations in the wake of the COVID-19 pandemic: a National Cohort Study. Gastroenterology 159, 1134–1136.e3 (2020). - PubMed
  177. Bajaj, J. S. et al. Comparison of mortality risk in patients with cirrhosis and COVID-19 compared with patients with cirrhosis alone and COVID-19 alone: multicentre matched cohort. Gut 70, 531–536 (2021). - PubMed
  178. Kim, D. et al. Predictors of outcomes of COVID-19 in patients with chronic liver disease: US multi-center study. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2020.09.027 (2020). - PubMed
  179. Sarin, S. K. et al. Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; the APCOLIS study (APASL COVID-19 Liver Injury Spectrum Study). Hepatol. Int. 14, 690–700 (2020). - PubMed
  180. Kates, O. S. et al. COVID-19 in solid organ transplant: a multi-center cohort study. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa1097 (2020). - PubMed
  181. Belli, L. S. et al. Protective role of tacrolimus, deleterious role of age and comorbidities in liver transplant recipients with Covid-19: results from the ELITA/ELTR multi-center European study. Gastroenterology https://doi.org/10.1053/j.gastro.2020.11.045 (2020) - PubMed
  182. Butt, A. A., Yan, P., Chotani, R. A., & Shaikh, O. S. Mortality is not increased in SARS-CoV-2 infected persons with hepatitis C virus infection. Liver Int. https://doi.org/10.1111/liv.14804 (2021). - PubMed
  183. Tillett, R. L. et al. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet Infect. Dis. 21, 52–58 (2021). - PubMed
  184. Qin, J. et al. Perioperative presentation of COVID-19 disease in a liver transplant recipient. Hepatology 72, 1491–1493 (2020). - PubMed
  185. Long, Q. X. et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat. Med. 26, 1200–1204 (2020). - PubMed
  186. Levitsky, J. et al. Risk for immune-mediated graft dysfunction in liver transplant recipients with recurrent HCV infection treated with pegylated interferon. Gastroenterology 142, 1132–1139.e1 (2012). - PubMed
  187. Friend, B. D. et al. Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma. Pediatr. Blood Cancer 64, e26682 (2017). - PubMed
  188. Duchini, A., Hendry, R. M., Nyberg, L. M., Viernes, M. E. & Pockros, P. J. Immune response to influenza vaccine in adult liver transplant recipients. Liver Transpl. 7, 311–313 (2001). - PubMed

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