BARCELONA—The emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) over the last two years has represented a serious challenge for healthcare professionals and liver patients worldwide. The B.1.1.529 (omicron) SARS-CoV-2 variant, being more transmissible and resistant to neutralization, rapidly displaced the B.1.617.2 (delta) variant. Besides omicron infection appears to be associated to milder symptoms, preliminary data on omicron natural immunity were still inconsistent by the time EASL position statements were published. The updated EASL position paper, although, provides a comprehensive review of liver-specific effects of COVID-19 infected patients with chronic liver disease, hepatobiliary cancer, and after liver transplantation.
Limited data on the course of COVID-19 in patients with pre-existing liver diseases or liver transplant recipients has left many unanswered questions. These patients require ongoing medical care and are likely to be at a higher risk of SARS-CoV-2 infection and develop severe symptoms. Based on current available data, this position paper aims to promote the best possible care for liver patients.
The paper published on 19 July 2022 in Journal of Hepatology provides recommendations for clinicians for the management and treatment of patients with chronic liver disease, hepatobiliary cancer, and liver recipients.
"This position paper summarizes the latest data on the impact of COVID-19 on the liver and issues guidance on the care of patients with chronic liver disease, hepatobiliary cancer, and previous liver transplantation, as the world continues to deal with the consequences of the COVID-19 pandemic", said co-author and Honorary Director of the Grifols Chair at EF CLIF Richard Moreau, Hôpital Beaujon, France.
In this paper, the authors cover a range of liver-related complications during and after COVID-19 including acute liver injury, secondary sclerosing cholangitis, autoimmune and autoimmune-like hepatitis. Recommendations include monitoring of liver biochemistry parameters (aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and bilirubin) during and after hospitalization.
"The EASL position paper brings together several experts who provide a comprehensive and up to date review on the current state of knowledge and provide guidance on the best way to interact with each of the issues surrounding patient management to prevent and treat COVID-19 infection in patients with liver disease", added co-author and Scientific Director of EF CLIF Rajiv Jalan, Professor of Hepatology, University College London, UK.
While there is evidence that patients with chronic liver disease with or without cirrhosis do not appear to be at increased risk of SARS-CoV-2 infection, patients with cirrhosis are at high risk of mortality due to COVID-19. The risk of death is even higher in alcohol-related liver disease (ALD). Experts thus recommend facilitating access to intensive care units when appropriate to minimize adverse outcomes in hospitalized liver patients. On the other hand, patients with non-alcoholic fatty liver disease (NAFLD) appear to be at an increased overall risk of developing severe COVID-19 symptoms which may be related to the presence of other comorbities including obesity, type 2 diabetis, cardiovascular disease, and hypertension. Despite patients with autoimmune liver disease do not appear to be at higher risk of SARS-CoV-2 infection and COVID-19 mortality, baseline use of glucocorticoids and azathioprine may be associated with severe COVID-19 symptoms—careful assessment of potential risks and benefits should be conducted before reducing or discontinuing treatment. Studies investigating the clinical impact of co-existing chronic viral hepatitis B or C with SARS-CoV-2 infection have shown that neither infection nor COVID-19-related mortality appear to be increased in these patients. However, patients with hepatocellular carcinoma are likely to have an increased risk of mortality after SARS-CoV-2 infection.
The lower antibody and T-cell responses of liver transplant patients to COVID-19 vaccination compared to the general population makes them particularly susceptible to SARS-CoV-2 infection. The recommendations for liver transplant recipients that develop COVID-19 include a dose reduction or discontinuation of the antimetabolites azathioprine or mycophenolate mofetil (MMF) when appropriate.
Moreover, the COVID-19 pandemic has had a great impact on the incidence and management of alcohol use disorder and ALD. Recommendations include raising awareness about the risks of harmful drinking at the local and population-level, and the urgent need for clear messages from public health authorities. The adoption of poor healthy diets together with a reduced physical activity during the pandemic has resulted in an increase in the prevalence of obesity and metabolic-related diseases which is likely to influence the development and progression of NAFLD. Also, experts here recommend that the goal of the World Health Organization (WHO) of eliminating viral hepatitis by 2030 should be pursued with no further delay, and encourage screening for viral hepatitis to be implemented alongside SARS-CoV-2 testing requirements and mass vaccination programs.
The authors of this paper also urge the need to return to the standard of care in the pre-COVID-19 pandemic period within hospitals and outpatient settings to reduce interruption of diagnostic procedures, screening programs, curative and/or palliative treatments, and liver transplant programs.
The paper provides recommendations for the treatment of COVID-19 in patients with chronic liver disease, hepatobiliary carcinoma and liver transplant recipients including antiviral therapies (remdesivir, nirmatrelvir/ritonavir, molnupiravir, monoclonal antibodies, and convalescent plasma), immunomodulatory therapies (corticosteroids, Janus kinase 1/2 inhibitors, and interleukin-6 receptor antagonists), medications under evaluation (e.g., sabizabulin), repurposed drugs with suspected antiviral or anti-inflammatory properties, and anticoagulation. Co-medications relevant for patients with chronic liver disease, hepatobiliary cancer and liver transplant recipients such as selective and non-selective beta-blockers, nucleos(t)ide analogues, direct-acting antivirals, calcineurin inhibitors, mTOR inhibitors, and immune checkpoint inhibitors are recommended not to be postponed, modified or discontinued after SARS-CoV-2 infection unless there are any contraindications. Mycophenolate mofetil, however, may be reduced or discontinued in liver transplant patients.
In this position paper, general public health prevention measures are also reviewed and several case reports of de novo autoimmune hepatitis after COVID-19 and on acute liver injury after COVID-19 vaccination presented. Data from observational studies evaluating immune responses after COVID-19 vaccination in liver transplant recipients or patients with chronic liver disease without previous SARS-CoV-2 infection are reported.
"Liver disease affects the immune system and therefore COVID-19 infection impacts negatively on the outcome of patients, particularly those with cirrhosis, autoimmune liver disease and patients who have had a liver transplant", explained Jalan. "The results of vaccination are also variable. With the emergence of new therapies for COVID-19, several novel approaches are now available", he added.
Other authors on the study are Thomas Marjot, Christiane S. Eberhardt, Tobias Boettler, Luca S. Belli, Marina Berenguer, Maria Buti, Mario U. Mondelli, Daniel Shouval, Thomas Berg, and Markus Cornberg.
Marjot, T.; Eberhardt, C.S.; Boettler, T.; Belli, L.S.; Berenguer, M.; Buti, M.; Jalan, R.; Mondelli, M.U.; Moreau, R.; Shouval, D.; Berg, T.; Cornberg, M. Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper, J. Hepatol. 2022. DOI: 10.1016/j.jhep.2022.07.008
About EF CLIF
The European Foundation for the Study of Chronic Liver Failure (EF CLIF) is a private non-profit organization connecting biomedical researchers and healthcare professionals with each other, with patients and patient associations, and with society. The fundamental purpose of EF CLIF, reflected in its founding Statements of 2015, is to advance knowledge and promote research and education in liver disease to improve the prognosis of patients living with chronic liver failure.
The Foundation has made pioneering efforts in conducting a series of large, international prospective studies that have been instrumental in reclassifying the trajectory of patients with chronic liver failure and led to the clinical, prognostic and pathophysiological definition of the syndrome referred to as “acute-on-chronic liver failure” characterized by acute decompensation of cirrhosis, severe systemic inflammation, organ failures, and high short-term mortality. We are inspiring best clinical practices for the management of patients with chronic liver failure and promoting a more sustainable and equitable healthcare system.
Within the Foundation, the European Association for the Study of the Liver (EASL) Chair supports research activities through the EASL-CLIF Consortium, a network of 117 tertiary care and university hospitals in 28 European countries. The Grifols Chair promotes translational studies in centers across Europe and North America within the framework of the European Network for Translational Research (ENTR) with 25 centers in 8 countries. Over the last five years, the Foundation has successfully expanded its geographical scope providing the context to support transcontinental collaborative research projects. The Global Projects chapter provides the framework to promote research in cirrhosis across the world with the aim to help to build consensus and ensure health equity worldwide.