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

Abstract

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/100× 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 10× 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 TNFα expression. Injection of the S1, but not S2, subunit of spike in mice induced hepatic lobular inflammation in activated macrophages. 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.

The amplification of CNS damage in Alzheimer's disease due to SARS-CoV2 infection

“…Although it is logical to assume there is more than one molecular mechanism, it was initially hypothesized that systemic spread of SARS-CoV2 infection from the lung and nasopharynx to the brain was the primary mechanism. However, many studies have documented that SARS-CoV2 RNA is rarely found in the bloodstream even in fatal COVID-19 and, importantly, the viral RNA is not detected in the brain in such cases [7] , [8] , [9] , [10] . As examples, qRT-PCR assays failed to detect SARS-CoV2 RNA in the CSF of COVID-19 patients with neurological complications [51] , and a larger study also indicated that viral RNA was not present in the brain in fatal COVID-19 cases, despite the widespread microvascular damage [52] .…”

“…Reduction of the latter protein, a key player in the blood brain barrier, has been proposed as a biomarker of Alzheimer's disease per se even in the absence of COVID-19 [42] . BCL6, BACH1, SHIP1, and BCL10 were chosen for study as each are targets of miR-155 , which we have shown is increased in the cells after the endocytosis of SARS-CoV2 spike protein [9] . Further, though miR-155 is not dysregulated in Alzheimer's disease, there was a relative decrease in BCL6 and BCL10 in the Alzheimer's disease brains versus controls [57] although the decrease was more pronounced in the COVID-19 brain tissues.…”

“…It is now well established that obesity and its related disease type II diabetes mellitus are the key risk factors for severe COVID-19 [1] , [2] and that the brain and heart are highly susceptible to pathologic changes [3] , [4] , [5] , [6] . Whereas it was initially assumed that systemic infectious SARS-CoV2 was responsible for non-pulmonary manifestations of severe COVID-19, it is now clear that infectious virus is rarely identified in the blood or organs besides the lung or nasopharyx [7] , [8] , [9] , [10] . Indeed, many investigators have documented that SARS-CoV2 spike protein per se , either in vitro , or in vivo in mouse models, can elicit the cytokine storm and direct CNS and cardiac damage typical of severe COVID-19 [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] .…”

Liver, NAFLD and COVID-19

“…Although comparisons of liver histology after COVID-19 infection between NAFLD versus controls have not been performed, a recent study reported histologic differences in fatal COVID-19 between patients with versus without alcohol use disorder (AUD). Specifically, people with AUD demonstrated not only 10-fold increased expression of ACE2 + cells, but also greater number of cells positive for viral spike protein compared to people without AUD [42]. Injection of the S1 subunit of spike protein in mice induced hepatic lobular inflammation [42].…”

“…Specifically, people with AUD demonstrated not only 10-fold increased expression of ACE2 + cells, but also greater number of cells positive for viral spike protein compared to people without AUD [42]. Injection of the S1 subunit of spike protein in mice induced hepatic lobular inflammation [42]. The discrepancies between studies may partially be explained by differences in the duration of infection, in patient characteristics, as well as in the post-mortem processing of the autopsy samples.…”