Correlation Between Clinical and Pathological Findings of Liver Injury in 27 Patients With Lethal COVID‐19 Infections in Brazil

Abstract

Liver test abnormalities are frequently observed in COVID-19 patients and are associated with worse prognosis. However, information is limited about pathological changes in the liver in this infection, so the mechanism of liver injury is unclear. Here we describe liver histopathology and clinical correlates of 27 patients who died of COVID-19 in Manaus, Brazil. There was a high prevalence of liver injury (elevated ALT and AST in 44% and 48% of patients, respectively) in these patients. Histological analysis showed sinusoidal congestion and ischemic necrosis in more than 85% of the cases, but these appeared to be secondary to systemic rather than intrahepatic thrombotic events, as only 14% and 22% of samples were positive for CD61 (marker of platelet activation) and C4d (activated complement factor), respectively. Furthermore, the extent of these vascular findings did not correlate with the extent of transaminase elevations. Steatosis was present in 63% of patients, and portal inflammation was present in 52%. In most cases hepatocytes expressed angiotensin converting enzyme 2 (ACE2), which is responsible for binding and entry of SARS-CoV-2, even though this ectoenzyme was minimally expressed on hepatocytes in normal controls. However, SARS-CoV-2 staining was not observed. Most hepatocytes also expressed ITPR3, a calcium channel that becomes expressed in acute liver injury. Conclusion: The hepatocellular injury that commonly occurs in patients with severe COVID-19 is not due to the vascular events that contribute to pulmonary or cardiac damage. However, new expression of ACE2 and ITPR3 with concomitant inflammation and steatosis suggests that liver injury may result from inflammation, metabolic abnormalities and perhaps direct viral injury.

Liver alterations and detection of SARS-CoV-2 RNA and proteins in COVID-19 autopsies

“…In serum, elevated enzyme activities (ALT, AST, GGT), concentrations of bilirubin, and concentrations of the inflammation indicator CRP were found; low lymphocyte counts, and high neutrophil-leukocyte counts were detected as well [ 9 , 54 – 58 ]. There was, however, no correlation found earlier between altered laboratory data and hepatopathologic findings in 27 and 100 autopsy cases [ 9 , 33 ], and which is the same in the recent study. Dyshemostasis characterized COVID-19, with increased prothrombin time, low platelet count, and high levels of interleukin 6, fibrinogens, and von Willebrand factor, among other abnormalities [ 52 ].…”

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

“…Components of the lectin and alternative pathway were activated in the kidneys of COVID-19 patients [ 46 ]. Deposits of the classical and alternative pathway were found in liver tissue of diseased COVID-19 patients [ 45 , 59 ], albeit C4d deposition was limited and C5d absent in one study measuring only these two components [ 59 ]. One study examined heart tissue of deceased COVID-19 patients, in which more C5b-9 was seen compared to non-COVID-19 controls [ 60 ].…”

Complement-mediated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A review

“…Interestingly, binding of the SARS-CoV-2 spike protein S1 and S2 subunits to heparan sulfate on cell surfaces and binding of the S and N proteins to lectin pathway molecules cause excessive activation of the alternative and lectin pathways, respectively, resulting in end-organ damage[ 47 , 48 ]. In contrast to the lung and small bowel findings, Santana et al [ 49 ] reported a low rate of C4d deposition (22%) in liver histopathologic specimens of 27 deceased patients, suggesting that hepatocellular injury is a result of systemic rather than intrahepatic thrombotic events.…”