Treating Liver Disease During COVID-19: New Recommendations

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The COVID-19 pandemic presents myriad challenges to hepatologists, gastroenterologists, transplant programs, primary care providers, and, of course, their patients. These frustrations are compounded by the fact that the virus' impact on the liver is not yet fully understood.

In order to advise healthcare providers on how best to serve patients and their families during these unprecedented times, the American Association for the Study of Liver Diseases (AASLD) recently released Clinical Insights for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic. The authors of this freely available resource prefaced it with the disclaimer that it represents only their collective opinions and has not been subjected to the methodical rigor of a practice guideline. Instead, it is a "living" document that will evolve and be updated as new information becomes available.

Nonetheless, it offers valuable clinical recommendations and policies to mitigate the impact of the COVID-19 pandemic on patients with liver disease and the healthcare providers who treat them. Here are some of the takeaways that we have found the most useful at our liver care center.

The Novel Coronavirus' Effects on the Liver: What We Know, What We Don't

SARS-CoV-2 binds to target cells through a functional receptor, angiotensin-converting enzyme 2, which is present on biliary and liver epithelial cells. Therefore, the liver is a potential target for infection.

Early reports suggest a 14%-53% incidence of liver injury in patients with COVID-19. This estimate is based on observation of elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels 1-2 times the upper limit of normal and modestly elevated total bilirubin levels early in the disease process. Liver injury in mild cases is usually transient and does not require specific treatment. However, rare cases of more severe acute hepatitis have been described. Reports of liver histologic changes have so far been limited, with documented nonspecific injury ranging from focal necrosis to moderate microvesicular steatosis with mild, mixed lobular, and portal activity.

The pathogenesis underlying such abnormal liver biochemistries is undefined. It may reflect a direct virus-induced cytopathic effect and/or immune damage from the provoked inflammatory response (cytokine storm/immune activation).

It is also not known whether patients with chronic liver disease such as viral hepatitis B and/or C may be more susceptible to liver damage from SARS-CoV-2, as was noted with the earlier SARS-CoV virus. Emerging data do suggest that patients with nonalcoholic fatty liver disease (NAFLD) may be at higher risk for severe COVID-19. It is not clear whether the risk is specific to NAFLD or to coexisting metabolic risk factors such as obesity, cardiovascular disease, and diabetes mellitus, all of which are associated with COVID-19 severity.

Assessing the Risk of COVID-19 in Our Patients

Taking these data into consideration, the AASLD document offers several recommendations.

The authors recommend that immunosuppressed patients (ie, those with autoimmune hepatitis and those post-transplant) should be closely monitored and prioritized for COVID-19 testing.

In addition, it should not be assumed that COVID-19 is the culprit in a patient presenting with acute liver injury. Other causes of elevated AST/ALT levels should be excluded, including viruses such as hepatitis A, B, and C, as well as muscle or cardiac injury, ischemia, and cytokine release syndrome. Similarly, for patients with autoimmune hepatitis or liver transplant recipients with active COVID-19 and elevated AST/ALT levels, do not presume disease flare or acute cellular rejection without biopsy confirmation.

It is also important to keep in mind that proposed COVID-19 therapeutic agents, such as remdesivir and tocilizumab, may in themselves be hepatotoxic.

The need to limit exposure of other patients and caregivers to a patient with COVID-19 is also emphasized. Therefore, transporting COVID-19–positive patients to undergo ultrasound or other advanced imaging should be avoided unless such testing is critical to management planning.

Given the potential for fecal-oral SARS-CoV-2 transmission, the AASLD has joined multiple other societies in strongly recommending that nonurgent procedures (eg, endoscopy, liver biopsy, transient elastography) be rescheduled.

Special Concerns Surrounding Liver Transplantation

One clear and immediate effect of the COVID-19 pandemic has been the decrease in liver donation and transplantation, an unintended consequence of which may be an increased rate of mortality of waitlisted patients.

There is limited information regarding the effects of SARS-CoV-2 infection in patients with decompensated cirrhosis or those awaiting liver transplantation. This makes the always complex decision as to whether to proceed with transplantation even more challenging.

Certain transplant centers may decide against providing organs to individual candidates at this time. The authors recommend that each center continuously assess the local situation and its impact. Special consideration could be given to high-risk waitlisted patients (ie, those with high Model for End-stage Liver Disease scores, risk of decompensation, or liver tumor progression). In addition, a reduction in organ recovery is expected because of COVID-19–related limitations on institutional resources and the evolving understanding of the risk of donor-derived disease transmission.

In order to limit the number of patients in the clinic, the recommendation is that centers evaluate only those patients with hepatocellular carcinoma or severe disease that need immediate liver transplant listing. For outpatients, the document supports the management strategy already employed by several programs: telemedicine in place of outreach clinics, judicious use of lab monitoring and imaging, and screening portals for patients coming in to the hospital.

Education, social work, dietitian, and financial consultation should also be conducted by video conference, telemedicine, or telephone. If possible, Internet-based education sessions for patients and family members can be deployed. We have found this approach to be well received at our institution.

There are additional recommendations for patients who have already undergone transplantation. It is postulated that because the immune response may be the main driver for pulmonary injury due to COVID-19, immunosuppression may, ironically, be protective. In fact, posttransplant immunosuppression was not a risk factor for mortality associated with the earlier severe acute respiratory syndrome (2002-2003) or Middle East respiratory syndrome (2012-present) outbreaks, but immunosuppression may prolong viral shedding in posttransplant patients with COVID-19.

Rapid pulmonary deterioration in patients with COVID-19 is postulated to be due to a systemic/pulmonary inflammatory response associated with increased serum interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha levels. It is further hypothesized that reducing the dosage or stopping immunosuppressants may cause a flare in a patient with autoimmune hepatitis or precipitate acute rejection in a liver transplant recipient.

These knowledge gaps have raised many questions among our transplant team. Therefore, we welcome the guidance to not reduce immunosuppression for asymptomatic posttransplant patients without known COVID-19. For immunosuppressed liver disease patients who do have COVID-19, the authors suggest reducing azathioprine or mycophenolate, and minimizing but not stopping calcineurin inhibitor dosage.

Impact on Clinical Research, Patient and Worker Safety

Due to quarantine-related travel restrictions and potential supply chain interruptions, the US Food and Drug Administration and the National Institutes of Health have posted guidance documents for the conduct of clinical trials during the COVID-19 pandemic. Patient safety, which is of highest importance, should be used to guide decisions affecting the trial, including recruitment, patient monitoring, assessments, and investigational product dispensing. A related recommendation is to not initiate new clinical trials unless they meet the definition of "essential."

Of course, ensuring the safety of all involved in the healthcare system is a paramount concern at the moment. The document provides advice/assurance to share with our patients, emphasizing the value of established prevention (hygiene, avoidance, travel restrictions), holding steady with immune suppression, and reporting all concerning symptoms.

There is widespread concern that the risks of exposing trainees to SARS-CoV-2 may outweigh the educational benefits. In order to allow trainees to meet regulatory requirements, the recommendation is to conduct all educational conferences via online platforms (eg, Zoom, Skype). After a few glitches, we have found this strategy to be very effective and well received. We have also followed recommendations to incorporate our trainees into telemedicine patient visits.

The SARS-CoV-2 infection rate of healthcare workers may be as high as 20%. In addition to protecting our patients, healthcare workers must take action to prevent COVID-19 infection and address the mental and physical well-being of our colleagues. As suggested in this document, we have staggered work shifts for physicians, providers, nurses, and staff, and created a "hepatologist/surgeon of the day" schedule.

As we all have learned, the strategies employed during this pandemic change daily, and we must adapt and adjust as new data emerge. I suggest that you visit the AASLD website for up-to-date COVID-19 resources.

And, of course, stay safe, stay sane, and stay sanitized.

William F. Balistreri, MD, is the Dorothy M. M. 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 has served as director of the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's for 25 years, and frequently covers gastroenterology-, liver-, and nutrition-related topics for Medscape. Dr Balistreri is currently editor-in-chief of The Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.

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