key: cord-1002627-t1m7dxzc authors: Schaefer, Esperance A. K.; Arvind, Ashwini; Bloom, Patricia P.; Chung, Raymond T. title: Interrelationship Between Coronavirus Infection and Liver Disease date: 2020-05-21 journal: Clin Liver Dis (Hoboken) DOI: 10.1002/cld.967 sha: 97c458e6fa019427199ee38b30d1d10e7c2231ac doc_id: 1002627 cord_uid: t1m7dxzc nan Liver injury in the setting of COVID-19-related illness poses a unique challenge to the clinician. First, there is often uncertainty whether there is preexisting undiagnosed liver disease. Second, many of the medications used to treat moderate and severe disease have their own profiles of liver toxicity. Finally, in the subset of patients who experience critical illness, multiple factors may influence the trajectory of liver injury. We summarize what is known about liver injury in COVID-19 and provide diagnostic clues to contributing factors to the liver biochemical profile. Several published studies have characterized the frequency and severity of liver biochemistry abnormalities on presentation, and a few have determined whether these abnormalities are associated with increased disease-related morbidity or death, as summarized in Table 1 . 9, 10, [12] [13] [14] [16] [17] [18] [19] [20] [21] [22] [23] [24] The largest published study to date encompassed 5700 hospitalized patients in New York and examined admission serologies: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were both frequently elevated (58.4% and 39.0% of subjects, respectively), and a separate large cohort found elevations to be more common in severe disease. 9 Two studies suggest that a higher proportion (44%-81%) of patients with underlying liver disease had abnormal liver biochemistries on admission. 11, 12 Elevations have been generally modest on admission, but available data suggest they become more frequently (93% in one series) and more severely deranged during the course of hospitalization. [12] [13] [14] Furthermore, liver impairment at admission has not been consistently associated with length of hospital stay, 11, 15 but has been found to correlate with time from illness onset to admission and with adverse outcomes. 14,15 Liver biochemistries do not appear to be associated with GI manifestations in COVID-19. 2 Aminotransferase elevation is the most common abnormality in patients presenting with COVID-19 (Table 1) . Published reports suggest that AST is more frequently elevated than ALT. 9, 10, 13, 22 Elevated alkaline phosphatase is rare, and an increase in bilirubin has less commonly been observed. However, interestingly, one report found elevated gamma-glutamyl transferase (GGT) levels in nearly 50% of subjects. 12 The trajectory of liver biochemistry changes during hospitalization for COVID-19 infection is marked by elevation in aminotransferases, with rare severe liver injury, and liver test abnormalities are more frequent in patients with more severe COVID-19. 12, 14 This pattern of liver injury is unlike that commonly observed in other forms of viral hepatitis, such as hepatitis B and C, but at least one report describes a similar pattern during influenza A/H1N1 influenza infection. 25, 26 In the prior severe acute respiratory syndrome (SARS) outbreak of 2003, a similar pattern of liver injury was observed. 27 The pattern of abnormal liver biochemistries characterized by an AST level greater than ALT, with accompanying GGT elevation, is also commonly encountered in both alcoholic liver disease and ischemic or congestive liver injury. 28 Thus, the liver injury observed in COVID-19 may reflect a direct viral effect, but other potential contributors must be considered, both at the time of initial presentation and during disease progression and management. Hepatic injury from SARS-CoV2 infection is observed from the time of initial contact with the medical system, suggesting that the primary insult is unrelated to medical management but rather due to either direct effect of the virus or a consequence of the systemic disease. However, the trajectory of liver injury is likely influenced by multiple additional factors (Fig. 2) . There may be a direct viral cytopathic effect, given the known presence of the ACE2 receptor in the liver. 5, 29 In SARS infection, viral RNA was detected in liver tissue. 30, 31 Further, recently published data suggest that mitochondrial proteins may directly interact with the virus, 32 providing a potential mechanistic explanation for the AST-dominant injury profile. Alternatively, the robust inflammatory response seen in COVID-19 may play a central role. The immune response to SARS-CoV-2 is characterized by very high levels of IL-6, 33 which has been implicated in both the inflammatory and the repair responses in liver disease. 34 Cardiomyopathy is a well-described consequence of COVID-19, occurring in 33% of individuals in one US series. 35 Thus, it is possible that cardiac dysfunction and review hepatic congestion contribute to hepatic injury in severe COVID-19 infection. Congestive hepatopathy may occur as a consequence of an acute cardiomyopathy, and it is commonly associated with elevations in aminotransferases and GGT. 36, 37 Severe ischemic hepatitis is a condition characterized by severe AST-predominant hepatitis 38 and may be observed in critically ill patients with COVID-19. The infrequently observed alkaline phosphatase elevation occurs late in COVID-19 disease progression and could reflect the cholestasis of sepsis, critical illness, 39 or medication effect. An increasing number of drugs are being investigated and empirically used in hospitalized patients with COVID-19. Many of these medications have a distinct risk, time course, and pattern of liver injury, as summarized in Table 2 . 41 Remdesivir (a nucleoside analog inhibitor of viral RNA polymerase, recently approved for use under a US Food and Drug Administration [FDA] Emergency Use Authorization) is experiencing growing use in COVID-19 trials and was associated with a 23% increase in liver enzymes in one small published report. 40 There is a high prevalence of abnormal liver biochemistries on presentation in patients with COVID-19. In light of the risk for additional injury due to the complications and management of moderate-to-severe disease, it is important to monitor hepatic enzymes during the course of disease. 42 If biochemistries worsen during disease progression, consideration must be given to possible contributors, including cardiac dysfunction, cytokine storm, ischemia, sepsis, and medication effect. 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