Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Investigative Medicine
First Advisor
Justice, Amy
Abstract
Background: Emerging data suggests severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may indirectly or directly cause acute liver injury (ALI) in patients with Coronavirus disease 2019 (COVID-19). In severe SARS-CoV-2 infection, activation of lung epithelial immune cells can lead to massive release of cytokines that can affect other organs, including the liver. Additionally, SARS-CoV-2 can induce local inflammation in the liver, either by activating liver-resident immune cells or by directly infecting cholangiocytes and hepatocytes after binding to angiotensin converting enzyme 2 (ACE2) receptors. This has raised the possibility of a predominantly biliary epithelial direct SARS-CoV-2-mediated damage as opposed to hepatocyte injury. It remains unclear if severe ALI in COVID-19 is associated with post-acute hepatic complications. In this dissertation we characterize patterns of severe ALI in COVID-19 patients: hepatocellular, cholestatic or mixed; and determine the association of these patterns with hepatic dysfunction (i.e., coagulopathy plus hyperbilirubinemia), and hepatic decompensation (i.e., ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage). Methods: We conducted a retrospective cohort study among patients with a positive polymerase chain reaction (PCR) or antigen test for SARS-CoV-2 between March 2, 2020, and October 19, 2021, using data from the Veterans Affairs (VA) healthcare system. Severe ALI was defined as 1) hepatocellular pattern, which was determined by elevations in AST>200 IU/ml and ALT≥40 IU/ml (to exclude AST leaked by muscle only); 2) cholestatic pattern, which was characterized by elevated ALKP>380 IU/ml; or 3) mixed pattern if both patterns occurred in the first 30 days after a positive SARS-CoV-2 test. Incidence rates (events per 1,000 person-years) of outcomes (severe ALI, hepatic dysfunction, and hepatic decompensation) with 95% CI were estimated overall and stratified by pre-existing chronic liver disease (CLD) status. We used Cox proportional hazards regression analyses with adjustments for COVID-19 severity to compare post-acute liver outcomes for each pattern group of ALI. Results: We included 173,142 COVID-19 patients in our analytic sample: 1,542 patients with an isolated hepatocellular pattern, 180 patients with an isolated cholestatic pattern and 121 patients with the mixed pattern of severe ALI. The patients included in this study were mostly male (90%), median age was 60 years and 58% were non-Hispanic white. At baseline, 30% of patients had pre-existing CLD. Most of the severe ALI events were within 2 weeks after COVID-19 diagnosis. The events appreciably declined with time until 30 days after COVID-19 diagnosis. In our multivariable Cox model, with adjustments for COVID-19 severity using the Veterans Administration COVID-19 (VACO) acute index, patients with pre-existing CLD were more likely to develop the isolated hepatocellular (aHR=2.65, [95% CI: 2.38–2.96], P<0.0001), cholestatic (aHR=2.98, [95% CI: 2.27–3.92] , P<0.0001), and mixed (aHR=4.74, [95% CI: 2.94–7.65] , P<0.0001) injury patterns, compared to those with no pre-existing CLD. Patients with the mixed pattern of injury had a 10-fold increase in unadjusted incidence rates of hepatic dysfunction compared to those with no severe ALI. In our multivariable Cox model, with adjustments for pre-existing CLD and COVID-19 severity, patients with severe ALI were more likely to develop incident hepatic dysfunction (isolated hepatocellular: aHR=2.19, [95% CI: 1.79–2.69], P<0.0001; isolated cholestatic: aHR=1.57, [95% CI: 1.05–2.35], P<0.0001; mixed: aHR=5.75, [95% CI: 4.23–7.81], P<0.0001) patterns, compared to patients with no severe ALI. The absolute risk of hepatic decompensation for patients with severe ALI was higher (isolated hepatocellular: 1.69%; isolated cholestatic: 4.44%; mixed: 9.92%) than for patients with no severe ALI (0.25%). In our multivariable Cox model, with adjustments for pre-existing CLD and COVID-19 severity, patients with cholestatic and mixed patterns of severe ALI were more likely to develop incident hepatic decompensation (isolated cholestatic: aHR=1.82, [95% CI: 1.04–3.18], P=0.04; mixed: aHR=5.61, [95% CI: 3.43–9.15], P<0.0001), compared to patients with no severe ALI. There was no significant association between the isolated hepatocellular pattern of severe ALI and hepatic decompensation (aHR=1.26, [95% CI: 0.86–1.83], P=0.23). Conclusions: Pre-existing CLD is associated with higher rates of severe ALI in COVID-19 patients independent of COVID-19 severity. Although the AST-predominant hepatocellular pattern is the most common pattern of severe ALI in COVID-19, it is less likely to be associated with hepatic decompensation. However, hepatocellular and cholestatic liver injury in COVID-19 have a synergistic effect on incident hepatic dysfunction and decompensation. The mixed pattern of severe ALI in COVID-19 is associated with incident hepatic dysfunction and decompensation even after adjustment for COVID-19 severity and pre-existing chronic liver disease. This mixed pattern represents a high-risk subphenotype with a 10% absolute risk of hepatic decompensation within 1 year of COVID-19 diagnosis.
Recommended Citation
Njei, Basile, "Patterns of Acute Liver Injury and Post-Acute Liver Sequelae of COVID-19" (2022). Yale Graduate School of Arts and Sciences Dissertations. 858.
https://elischolar.library.yale.edu/gsas_dissertations/858
