Abnormal Liver Function Tests in Patients With COVID‐19: Relevance and Potential Pathogenesis

Abstract

Potential conflict of interest: Dr. Bodewes advises Vertex. Dr. Strazzabosco advises Bayer and Engitix. The current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to over 6 million cases and over 370,000 deaths as of June 1, 2020.(1) Although most patients infected with SARS‐CoV‐2 develop only mild symptoms, a minority of patients require hospitalization and intensive care.(2) Based on the available clinical data, abnormal liver function tests (LFTs) are frequently observed in patients with coronavirus disease 2019 (COVID‐19), of which the underlying pathogenesis is incompletely understood. We reviewed the available information on the prevalence, nature, relevance, and the potential pathogenesis of altered LFTs in patients with COVID‐19. Epidemiology of Abnormal LFTs in Patients With COVID‐19 Liver function tests include measures of hepatocyte injury (aspartate transferase [AST] and alanine transferase [ALT]), bile duct injury or cholestasis (alkaline phosphatase [ALP] and gamma‐glutamyltransferase [GGT]), markers of hepatic clearance/biliary secretion capacity (bilirubin), as well as measures of synthetic capacity (prothrombin time and albumin). LFTs are not necessarily liver‐specific. It has been suggested that elevated aminotransferases in COVID‐19 could also originate from myositis rather than liver injury.(3) In a large descriptive study, the muscle damage marker creatinine kinase was elevated in 14% of patients with COVID‐19.(4) Hypoalbuminemia was reported in 55% of hospitalized patients with COVID‐19(5) and was associated with disease severity.(6) Hypoalbuminemia was an independent predictor of mortality.(7) Lower levels of pre‐albumin in patients with severe COVID‐19 were reported, suggesting decreased hepatic synthesis.(5) In the context of inflammation, hypoalbuminemia may also reflect albumin extravasation as a consequence of increased capillary permeability.(8) Additional factors that could explain the observed hypoalbuminemia in severe COVID‐19 are increased catabolism and malnutrition. The prevalence of ALT elevations among patients with COVID‐19 ranged between 4% and 33% in Chinese cohorts (weighted average: 19%), but was as high as 39% in a large cohort from the New York City area(5,9‐21) (Fig. 1). ALT elevations were generally mild, defined as less than 5 times the upper reference limit.(9,10,14‐19,21‐34) The prevalence of AST elevations ranged between 4% and 53% in Chinese cohorts (weighted average: 21%) and was 58% in the US cohort(4,5,9‐16,18,19,21,22,24,25,29,34,35) (Fig. 1). AST elevations were similarly less than 5 times the upper reference limit.(9,10,14‐16,18,19,21‐31,34,36) AST and ALT elevations had also been reported in patients with SARS caused by SARS‐CoV.(37) Several case reports have described severe LFT abnormalities(18,38,39) or acute‐on‐chronic(40,41) liver failure in patients with COVID‐19. Zhang et al.(33) reported that 1 of 82 deceased patients with COVID‐19 had a hepatic cause of death, although it was not clear whether this patient had pre‐existing liver disease.FIG. 1: Percentage of hospitalized COVID‐19 patients with AST or ALT elevations on admission. The studies summarized included patients with all levels of disease severity. The size of the dots reflects the relative number of patients included in each study. The upper panels represent Chinese cohorts, whereas the lower panel represents a US cohort. The weighted averages are represented by the vertical black lines and refer to the Chinese cohorts.Elevated ALP was reported in 2%‐5% of patients,(5,11,25,42) and elevated GGT was reported in 13%‐54% of patients (weighted average: 23%).(5,11,19,42) The prevalence of total bilirubin elevations ranged between 1% and 18% of patients with COVID‐19 on admission.(4,5,15,16,18,25,35,43) It should be realized, however, that pre‐existing liver disease was not comprehensively described in any of these studies. Stratification of patients with COVID‐19 according to disease severity, including the extent of respiratory distress and the need for intensive care unit (ICU) admission, indicated that plasma ALT and AST were elevated more frequently and to a greater extent in patients with severe COVID‐19 compared to those with mild disease.(4,5,9,14,22,23,29,31,43‐47) This was also the case for patients with SARS during the 2002‐2004 SARS outbreak.(37) The prognostic value of abnormal LFTs in COVID‐19 is unclear. Some studies found that abnormal LFTs, particularly elevated AST and (peak) ALT, are associated with increased disease severity and mortality,(17,20,46,47) whereas other studies did not find an association with mortality,(48) disease progression,(5) ICU admission,(27,48) or length of hospital stay.(11) Potential Pathogenesis of Abnormal Liver Function Tests in Patients With COVID‐19 Hepatic Infection With SARS‐CoV‐2 SARS‐CoV‐2 uses the angiotensin‐converting enzyme 2 (ACE2) as docking and entry receptor on host cells.(49) Transmem