From the Journals

Liver disease associated with worse COVID-19 outcomes



A growing body of evidence suggests that patients with COVID-19 and preexisting liver disease face increased risks of decompensation and mortality, according to a review of recent literature.

The review aimed to bring together the best approaches for caring for patients with preexisting liver conditions based on recommendations from three major hepatology societies. Findings in included studies could guide clinical decision-making, but a reliable framework for patient management has yet to be established, most likely because of limited research, according to lead author Abdul Mohammed, MD, of Case Western Reserve University, Cleveland, and colleagues.

The relationship between chronic liver diseases and “COVID-19 is not well documented in the literature,” Dr. Mohammed and colleagues wrote in the Journal of Clinical Gastroenterology. “The intricate interplay between immune dysfunction in preexisting liver diseases and the immune dysregulation triggered by the SARS-CoV-2 virus needs further evaluation.”

Such knowledge gaps likely explain the inconsistencies in recommendations between major hepatology societies, including clinical guidance from the American Association for the Study of Liver Disease, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver.

Both the literature review and the societal guidance address nonalcoholic fatty liver disease (NAFLD), hepatitis B virus (HBV) infection, autoimmune hepatitis, hepatocellular carcinoma (HCC), cirrhosis, and liver transplantation.

Dr. Mohammed and colleagues first offered an update of the relationship between COVID-19 and liver pathology. While it is clear that SARS-CoV-2 gains hepatic access through binding to ACE2 receptors in bile duct epithelial cells, it remains unclear whether this results in direct hepatic injury or indirect damage from virus-mediated cytokine release. Regardless, more than 90% of patients hospitalized for COVID-19 may develop increased levels of ALT and AST, and these elevations “appear to mirror disease severity,” the investigators wrote.

They noted that severity of COVID-19 appears to correlate with type of preexisting liver disease. For example, one study in the review associated NAFLD with a significantly increased risk of progressive COVID-19 (odds ratio, 6.4; 95% confidence interval, 1.5-31.2), and it also found that patients with NAFLD had longer duration of viral shedding than those without (17 vs. 12 days). Although the AASLD and APASL give no specific recommendations, the EASL recommends prioritizing COVID-19 patients with NAFLD.

Cirrhosis has been associated with a fourfold increased risk of mortality (relative risk, 4.6; 95% CI, 2.6-8.3) According to data from two international self-reporting registries, and, likelihood of death appears to move in tandem with Child-Turcotte-Pugh scores. Decompensated cirrhosis appears to predispose patients to having pulmonary complications, but more studies exploring this correlation need to be performed, according to the review authors. One study found that acute-on-chronic liver failure or acute decompensation occurred in 20% of patients who had COVID-19 and cirrhosis. It’s little surprise, then, that both the AASLD and the EASL recommend prioritizing in person evaluation for patients with decompensated cirrhosis.

Chronic HBV infection has also been associated with a higher COVID-19 mortality rate, although Dr. Mohammed and colleagues suggested that “larger studies are needed.” The review notes that the three societies recommend initiating HBV treatment only if there is clinical suspicion of hepatitis flare.

Findings are also cloudy among patients with autoimmune hepatitis and liver transplant recipients; however, the investigators noted that COVID-19 causes tissue damage primarily through cytokine release, and suggested that “immunosuppression can potentially curb this response.” Even so, recommendations from leading hepatology societies allude to a safe middle ground of immunosuppression, albeit with indistinct borders. All three caution against withdrawing immunosuppression, but the societies each describe tailoring regimens in different ways and for different patients, emphasizing continued corticosteroid treatments, according to the review.

Guidance also varies for management of HCC. “Since the tumor doubling time is 4-8 months and current guidelines recommend screening every 6 months, in patients at lower risk for developing HCC, a 2-month delay in ultrasound surveillance has been suggested by the AASLD,” the review authors noted. “In patients with a high risk of developing HCC, 6-month interval screening should be continued.” The AASLD recommends proceeding with treatment with newly diagnosed HCC, the EASL suggests that checkpoint inhibitors should be withheld and locoregional therapies should be postponed, and the APASL calls for a less frequent schedule of tyrosine kinase inhibitors and immunotherapy.

“COVID-19 patients with the preexisting liver disease face a higher risk of decompensation and mortality,” the review authors concluded. “We presented the most up-to-date literature on preexisting liver disease and its interaction with COVID-19.”

Dr. Wajahat Mehal

While such discrepancies may remain unresolved until further data are available, Wajahat Mehal, MD, PhD, director of the fatty liver disease program at Yale University, New Haven, Conn., suggested that clinicians remain vigilant for nonalcoholic steatohepatitis (NASH), which is common among overweight and obese individuals, an overrepresented group among those hospitalized for COVID-19.

“This is of great significance because patients with various forms of liver disease have a worse outcome with COVID-19,” Dr. Mehal said. “When seeing a patient with COVID-19 it is therefore important to ask if they have underlying liver disease, with attention paid to NASH. This can be approached by seeing if they have any evidence of abnormal liver function tests before the onset of COVID and any evidence of abnormal liver imaging. The Fib-4 test is a good screening tool for the presence of advanced liver fibrosis and a positive result should lead to more specific tests of liver fibrosis status such as fibroscan.”

The investigators reported no conflicts of interest. Dr. Mehal reported having nothing to disclose.

For the latest clinical guidance, education, research and physician resources about coronavirus, visit the AGA COVID-19 Resource Center at

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