COVID-19's Impact -- Don't Overlook the Liver

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New data from Chinese colleagues working at the forefront of the COVID-19 outbreak, and studies of earlier viral outbreaks, provide important insight into the hepatotoxic and gastrointestinal implications of this pandemic.

Respiratory symptoms are the most common presentation, but they're not the only early signs of COVID-19. Diarrhea, nausea, vomiting, and abdominal pain were well documented and often preceded respiratory symptoms in a subset of 138 consecutive hospitalized patients in Wuhan, China.

A recently published study also indicates that COVID-19 was detected in the stool of over 50% of infected hospitalized patients. Investigators found that the lamina propria of the stomach, duodenum, and rectum was edematous with infiltrating plasma cells and lymphocytes. Viral host receptor angiotensin-converting enzyme 2 (ACE2) and viral nucleocapsid protein stained positive in specimens, making gastrointestinal infection with COVID-19—and fecal-oral transmission—likely. Fecal shedding of viral RNA was also found in 20% of patients with COVID-19, despite real-time reverse transcriptase polymerase chain reaction testing from two sequential respiratory tract specimens collected at least 24 hours apart being negative. These results have a clear impact regarding transmission precautions, especially in hospitalized patients.

Liver impairment is another emerging concern with COVID-19, as it was with the similar novel coronavirus, severe acute respiratory syndrome (SARS). According to a 2004 report, up to 60% of patients with SARS had liver impairment, with liver biopsy specimens demonstrating viral nucleic acids and injury. These authors noted that this may have been the result of drug-induced liver injury, given that most of these patients were treated with high doses of potentially hepatotoxic antivirals, antibiotics, and steroids.

A recent publication observed that 54% of patients hospitalized for COVID-19 at a single center in China had elevated gamma-glutamyl transferase (GGT). ACE2 expression is enriched in cholangiocytes, suggesting that COVID-19 might actually cause a higher risk for biliary injury over hepatocyte injury, as supported by these observed GGT elevations

Implications of Hepatic Dysfunction in Severe COVID-19

Individuals at high risk for severe COVID-19 are typically of older age and/or present with comorbid conditions such as diabetes, cardiovascular disease, and hypertension. This is also the same profile for those at increased risk for unrecognized underlying liver disease, especially nonalcoholic fatty liver disease. This could make them more susceptible to liver injury from the virus, medications used in supportive management, or hypoxia.

Immune system overreaction accompanies disease progression, which can also independently lead to organ failure. It is well established that liver enzymes rise during systemic infections. Seasonal influenza is not known to cause hepatitis. However, a retrospective study comparing cohorts infected with either seasonal influenza or the more pathogenic influenza A/H1N1 behind a 2009 pandemic found that the latter resulted in a greater degree of inflammation/C-reactive protein elevation. Influenza animal models suggest that hepatic oxidative stress leading to injury is the primary event, not viral replication, although injury from virus-specific CD8+T cells might also be at play.

In considering the clinical implications of these data, we need to have a high suspicion for COVID-19 in patients who present with gastrointestinal (not just respiratory) symptoms. Such patients should be tested and isolated similar to the procedure for both respiratory and fecal-oral infections until confirmatory tests return. Isolation might need to be prolonged beyond when respiratory tract specimens are negative, especially in those with gastrointestinal manifestations. In our attempts to accomplish social isolation, individuals with underlying liver disease, or risks for liver disease, should be treated similarly to other high-risk groups.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a Web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair for the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.

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