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

Liver test abnormalities are frequently observed in patients with coronavirus disease 2019 (COVID-19) 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 alanine aminotransferase and aspartate aminotransferase 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 severe acute respiratory syndrome coronavirus 2 (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 inositol 1,4,5-triphosphate receptor 3 (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.

Significant Liver Injury During Hospitalization for COVID-19 Is Not Associated With Liver Insufficiency or Death.

BACKGROUND & AIMS: Coronavirus-19 disease (COVID-19) is associated with hepatocellular liver injury of uncertain significance. We aimed to determine whether development of significant liver injury during hospitalization is related to concomitant medications or processes common in COVID-19 (eg, ischemia, hyperinflammatory, or hypercoagulable states), and whether it can result in liver failure and death. METHODS: There were 834 consecutive patients hospitalized with COVID-19 who were included. Clinical, medication, and laboratory data were obtained at admission and throughout hospitalization using an identified database. Significant liver injury was defined as an aspartate aminotransferase (AST) level 5 or more times the upper limit of normal; ischemia was defined as vasopressor use for a minimum of 2 consecutive days; hyperinflammatory state was defined as high-sensitivity C-reactive protein value of 100 mg/L or more, and hypercoagulability was defined as D-dimer 5 mg/L or more at any time during hospitalization. RESULTS: A total of 105 (12.6%) patients developed significant liver injury. Compared with patients without significant liver injury, ischemia (odds ratio [OR], 4.3; range, 2.5-7.4; P < .0001) and tocilizumab use (OR, 3.6; range, 1.9-7.0; P = .0001) were independent predictors of significant liver injury. Although AST correlated closely with alanine aminotransferase (R = 0.89) throughout hospitalization, AST did not correlate with the international normalized ratio (R = 0.10) or with bilirubin level (R = 0.09). Death during hospitalization occurred in 136 (16.3%) patients. Multivariate logistic regression showed that significant liver injury was not associated with death (OR, 1.4; range, 0.8-2.6; P = .2), while ischemic (OR, 2.4; range, 1.4-4.0; P = .001), hypercoagulable (OR, 1.7; range, 1.1-2.6; P = .02), and hyperinflammatory (OR, 1.9; range, 1.2-3.1; P = .02) disease states were significant predictors of death. CONCLUSIONS: Liver test abnormalities known to be associated with COVID-19 are secondary to other insults, mostly ischemia or drug-induced liver injury, and do not lead to liver insufficiency or death.

Abnormal Liver Tests in COVID-19: A Retrospective Observational Cohort Study of 1,827 Patients in a Major U.S. Hospital Network.

BACKGROUND AND AIMS: The coronavirus-19 disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 virus, is associated with significant morbidity and mortality attributable to pneumonia, acute respiratory distress syndrome, and multiorgan failure. Liver injury has been reported as a nonpulmonary manifestation of COVID-19, but characterization of liver test abnormalities and their association with clinical outcomes is incomplete. APPROACH AND RESULTS: We conducted a retrospective cohort study of 1,827 patients with confirmed COVID-19 who were hospitalized within the Yale-New Haven Health System between March 14, 2020 and April 23, 2020. Clinical characteristics, liver tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin [TBIL], and albumin) at three time points (preinfection baseline, admission, and peak hospitalization), and hospitalization outcomes (severe COVID-19, intensive care unit [ICU] admission, mechanical ventilation, and death) were analyzed. Abnormal liver tests were commonly observed in hospitalized patients with COVID-19, both at admission (AST 66.9%, ALT 41.6%, ALP 13.5%, and TBIL 4.3%) and peak hospitalization (AST 83.4%, ALT 61.6%, ALP 22.7%, and TBIL 16.1%). Most patients with abnormal liver tests at admission had minimal elevations 1-2× the upper limit of normal (ULN; AST 63.7%, ALT 63.5%, ALP 80.0%, and TBIL 75.7%). A significant proportion of these patients had abnormal liver tests prehospitalization (AST 25.9%, ALT 38.0%, ALP 56.8%, and TBIL 44.4%). Multivariate analysis revealed an association between abnormal liver tests and severe COVID-19, including ICU admission, mechanical ventilation, and death; associations with age, male sex, body mass index, and diabetes mellitus were also observed. Medications used in COVID-19 treatment (lopinavir/ritonavir, hydroxychloroquine, remdesivir, and tocilizumab) were associated with peak hospitalization liver transaminase elevations >5× ULN. CONCLUSIONS: Abnormal liver tests occur in most hospitalized patients with COVID-19 and may be associated with poorer clinical outcomes.