The histologic and molecular correlates of liver disease in fatal COVID-19 including with alcohol use disorder

Hepatic disease is common in severe COVID-19. This study compared the histologic/molecular findings in the liver in fatal COVID-19 (n = 9) and age-matched normal controls (n = 9); three of the fatal COVID-19 livers had pre-existing alcohol use disorder (AUD). Controls showed a high resident population of sinusoidal macrophages that had variable ACE2 expression. Histologic findings in the cases included periportal/lobular inflammation. SARS-CoV2 RNA and nucleocapsid protein were detected in situ in 2/9 COVID-19 livers in low amounts. In 9/9 cases, there was ample in situ SARS-CoV-2 spike protein that co-localized with viral matrix and envelope proteins. The number of cells positive for spike/100x field was significantly greater in the AUD/COVID-19 cases (mean 5.9) versus the non-AUD/COVID-19 cases (mean 0.4, p < 0.001) which was corroborated by Western blots. ACE2+ cells were 10x greater in AUD/COVID-19 livers versus the other COVID-19/control liver samples (p < 0.001). Co-expression experiments showed that the spike protein localized to the ACE2 positive macrophages and, in the AUD cases, hepatic stellate cells that were activated as evidenced by IL6 and TNF alpha expression. In-jection of the S1, but not S2, subunit of spike in mice induced hepatic lobular inflammation in activated mac-rophages. It is concluded that endocytosed viral spike protein can induce hepatitis in fatal COVID-19. This spike induced hepatitis is more robust in the livers with pre-existing AUD which may relate to why patients with alcohol abuse are at higher risk of severe liver disease with SARS-CoV2 infection.