COVID-19 and liver disease: answering key questions
For those of us who are treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression / transplantation on sensitivity and outcomes to COVID-19. Now data is emerging to help answer some of the key questions regarding COVID-19 and the liver.
Does the virus itself cause liver disease?
The answer to this question is still a bit unclear. Several early reports[1,2,3,4,5,6,7,8,9,10,11] said hospitalized patients with SARS-CoV-2 infection frequently had elevated liver chemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, but the magnitude of the elevation in enzymes was generally reported to be mild and normalized as symptoms of COVID-19 improved.
Not surprisingly, patients with severe hepatic impairment (defined by AST and ALT levels above five times the upper limit of normal) were more likely to have a complicated clinical course, including elevated inflammatory markers and requiring admission to an intensive care unit (ICU), replacement therapy and / or intubation. Currier and his colleagues reported that patients with COVID-19 who had high levels of AST and ALT had significantly higher chances of these same adverse outcomes and of death.
This reflects the multifactorial pathogenesis of elevated enzymes, including a direct harmful effect of the virus on hepatocytes, cytokines or immune-mediated liver injury, drug hepatoxicity or hypoxia, and systemic inflammation.
Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting death rate of 74%. Wagner and his colleagues suggested that the pattern of maximal enzyme elevation was prognostic for serious clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed profile (elevations of AST / ALT and alkaline phosphatase) performed worse than those with a hepatocellular phenotype (isolated elevation of AST and / or ALT).
Serious liver damage associated with SARS-CoV-2 infection is rare in children. However, elevated levels of AST and ALT may be observed in association with multisystem inflammatory syndrome.[12,13,14,15]
Are patients with pre-existing chronic liver disease more susceptible to side effects?
Early observations suggest that patients with chronic liver disease, such as cirrhosis, who contract SARS-CoV-2 have high rates of hospitalization and death. However, it is not clear whether all of these patients are affected or whether certain subgroups are at higher risk.
In results they hoped would allow for better risk stratification and better personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk of all-cause mortality from COVID-19. Separate presentations during Digestive Disease Week 2021 confirmed that patients with pre-existing liver disease had a three-fold rate of death, thromboembolism, acute respiratory distress syndrome, and severe course of COVID-19 disease. higher, and that patients with both COVID-19 and cirrhosis had significantly higher mortality rates (18% vs. 13%), intensive care admissions (46% vs. 34%), and longer lengths of stay than those without cirrhosis.
Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with serious illness from COVID-19. Hepatic steatosis has also been reported to be associated with poorer outcomes in patients with liver damage and SARS-CoV-2 infection and a higher proportion of patients with NAFLD required mechanical ventilation. during their hospital stay (47% vs. 17%) and had increased mortality (41% vs. 17%).
Do immunocompromised patients face unique risks of infection?
Data from a limited case series, patient registries, and multi-center international studies concluded that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (HAI) was comparable to that seen in non-immunocompromised people. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity, as immunosuppression can actually protect against the inappropriate immune response, or cytokine storm, engendered during severe infection. by SARS-CoV-2.
The complexity of this relationship is further illustrated by a report by Bril and colleagues who described a case of AIH that developed after a patient received a COVID-19 vaccine. The authors were careful to point out that a causal relationship between vaccine administration and the onset of HAI cannot be proven.
What is the impact on liver transplant recipients?
Results are limited regarding clinical outcomes and disease severity from SARS-CoV-2 infection in liver transplant recipients, but early reports have raised concerns about high outcome rates unwanted.[16,17,18,19,20,21,22,23,24,25]
Tien and his colleagues have reported an increased risk of death from COVID in liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk of hospitalization, but no higher risk of mortality, thrombosis, or intensive care requirements. compared to patients with COVID-19 who had not had a liver transplant. . Advanced age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and mortality in liver transplant recipients.
Clearly, more data is needed to assess the influence of liver transplantation in patients with COVID-19; however, some risk / protective factors have been cited. For example, Belli and colleagues reported that using tacrolimus was associated with better results. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
Do COVID-19 vaccines work differently in patients with liver disease?
Unfortunately, we were unable to answer many of our patients’ questions regarding the efficacy, safety and durability of vaccines. Data is limited because immunocompromised patients were excluded from phase 3 trials of COVID-19 vaccines.
We also need more clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with BNT162b2 mRNA vaccine (BioNTech / Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were only detectable in 48% of patients versus 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there is no data on the correlation of protection against SARS-CoV-2 with antibody titers.
Additional data will be needed to assess the vaccine’s efficacy in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we look forward to studies that will determine if booster doses are needed.
What is the result ?
In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.
As we await further clarity, there are a few practical points of clinical relevance that we take away from the literature, the recently released joint statement on COVID-19 vaccination in solid organ transplant recipients, and the American Association. for the study of liver disease (AASLD) consensus statement. These suggest that clinicians take the following actions:
When evaluating patients infected with SARS-CoV-2 and elevated levels of AST and ALT, the first objective is to exclude etiologies unrelated to COVID-19, especially other viruses and drug-induced damage, as well as non-hepatic causes (eg, myositis, heart damage, ischemia).
Reduction of immunosuppression in SARS-CoV-2 infected patients with IAH should be carefully considered and generally undertaken only in patients with severe disease.
Pre-transplant vaccination against SARS-CoV-2 is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, in order to reduce the exposure of these patients, as well as that continued compliance with protective measures (masking and social distancing).
Continuation of a stable post-transplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk of organ rejection until more complete data are available.
For updated answers to evolving guidelines, visit the AASLD Resource Center.
William F. Balistreri, MD, is the Dorothy MM Kersten Professor of Pediatrics; Director Emeritus, Pediatric Liver Care Center; medical director emeritus, liver transplantation; and Professor, University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center. He was director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers topics related to gastroenterology, liver and nutrition for Medscape. Dr Balistreri is currently editor-in-chief of Pediatric Journal, after having been editor-in-chief of several journals and manuals. He also became the first pediatrician to serve as president of the American Association for the Study of Liver Disease. In his spare time, he coaches lacrosse youth.
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