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Abnormal Liver Tests in COVID-19: A Retrospective Observational Cohort Study of 1827 Patients in a Major U.S. Hospital Network
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from Jules: many HIV+ have elevated liver tests which are thought could be due to non viral hepatitis, NASH or fatty liver, or HIV. This could be a subgroup at greater risk for bad COVID outcomes but so far I have not seen research sort out this potential risk factor for HIV+.
"......an association between abnormal liver tests and severe COVID-19, including ICU admission, mechanical ventilation, and death; associations with age, male gender, BMI, 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 >5x ULN."
Hepatology July 29 2020 - Melanie A. Hundt, MD 1, Yanhong Deng, MPH 2, Maria M. Ciarleglio, PhD 2, Michael H. Nathanson, MD PhD 1,3, Joseph K. Lim, MD 1,3
1 Department of Medicine, Yale School of Medicine, New Haven, CT; 2 Yale Center for Analytical Sciences, Yale School of Public Health, New Haven, CT; 3 Yale Liver Center and Section of Digestive Diseases, Yale School of Medicine, New Haven, CT.
Abstract
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is associated with significant morbidity and mortality due to pneumonia, acute respiratory distress syndrome (ARDS) and multiorgan failure. Liver injury has been reported as a non-pulmonary manifestation of COVID-19 but characterization of liver test abnormalities and their association with clinical outcomes is incomplete. We conducted a retrospective cohort study of 1827 patients with confirmed COVID-19 who were hospitalized within the Yale-New Haven Health System (YNHHS) between March 14, 2020 and April 23, 2020. Clinical characteristics, liver tests (AST, ALT, ALP, TBIL, albumin) at three time points (pre-infection baseline, admission, peak hospitalization), and hospitalization outcomes (severe COVID-19, ICU admission, mechanical ventilation, 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%, TBIL 4.3%) and peak hospitalization (AST 83.4%, ALT 61.6%, ALP 22.7%, TBIL 16.1%). Most patients with abnormal liver tests at admission had minimal elevations 1-2x ULN (AST 63.7%, ALT 63.5%, ALP 80.0%, TBIL 75.7%). A significant proportion of these patients had abnormal liver tests pre-hospitalization (AST 25.9%, ALT 38.0%, ALP 56.8%, 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 gender, BMI, 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 >5x ULN.
Conclusion: Abnormal liver tests occur in most hospitalized patients with COVID-19 and may be associated with poorer clinical outcomes.
This study represents one of the largest reports of liver tests and clinical outcomes to date in hospitalized patients with confirmed SARS-CoV-2 infection in the U.S. Although fever, cough, and shortness of breath have been identified as the most common symptoms in affected individuals, liver test elevation has been identified as one of a growing spectrum of non-pulmonary manifestations described in COVID-19, which may potentially be attributable to hepatic expression of the primary viral entry receptor, angiotensin converting enzyme II (ACE2) [24-25]. Based on a large systematic review and meta-analysis (17 studies, 2711 patients), liver test abnormalities are estimated to occur in approximately 15% of patients [26].
Severe COVID-19 infection was more likely to be seen in patients with increased age, male gender, higher BMI, and abnormal liver tests. Most patients with abnormal liver tests had minimal elevations pre-hospitalization or at admission, but an important subset of patients experienced more extreme elevations of liver transaminases (>5x ULN) during hospitalization (AST 16.6%, ALT 20.6%), although this was less commonly observed with other liver tests (ALP 1.5%, TBIL 3.9%).
Baseline pre-hospitalization values were available in greater than 70% of patients with abnormal liver tests at admission (Table 3) and were abnormal in a significant proportion (AST 25.9%, ALT 38.0%, ALP 56.8%, TBIL 44.4%, albumin 27.1%). Predictors of abnormal liver tests at hospital admission are summarized in Table 4, including age, male gender, BMI, diabetes mellitus, and pre-hospitalization abnormal liver tests. Predictors of peak hospitalization abnormal liver tests >5x ULN are summarized in Table 5, including age, male gender, BMI, diabetes mellitus, and medications (lopinavir/ritonavir, hydroxychloroquine, remdesivir, and tocilizumab).
The association between admission and peak hospitalization liver tests and clinical outcomes (ICU admission, mechanical ventilation, and death) are summarized in Table 6. On multivariate analysis, male gender, BMI, diabetes mellitus, and abnormal liver tests were associated with ICU stay, mechanical ventilation, and death.
The relationship between pre-hospitalization and admission liver tests in patients with severe and non-severe COVID-19 is illustrated in Figure 1. A significant increase in transaminases and significant decrease in albumin were observed regardless ofseverity; a significant increase in total bilirubin was seen in patients with severe COVID-19. After exclusion of patients with abnormal liver tests prior to hospital admission, key associations between abnormal liver tests at admission and severe COVID-19, as well as between abnormal liver tests at peak hospitalization and clinical outcomes (ICU admission, mechanical ventilation) were sustained on multivariate analysis (Supplementary Tables 1-3).
On hospital admission, abnormal liver tests were
commonly observed (AST 66.9%, ALT 41.6%, ALP 13.5%, TBIL 4.3%, albumin 56.7%). Liver test abnormalities were defined as per YNHHS laboratory reference range standards: AST >33 U/L, ALT > 34 U/L, ALP >122 U/L, TBIL
>1.2 mg/dL, albumin <3.5 mg/dL.
Abnormal liver tests were commonly observed in hospitalized patients with COVID-19 both pre-hospitalization (AST 20.3%, ALT 19.1%, ALP 13.4%, TBIL 4.1%, albumin 27.0%) and peak hospitalization (AST 83.4%, ALT 61.6%, ALP 22.7%, TBIL 16.1%, albumin 86.6%).
The current report has several key findings. First, abnormal liver tests are very common in hospitalized patients with COVID-19, and possibly more common in U.S. patients than previously reported in China. Whereas the prevalence of abnormal liver tests in studies from China was estimated at 14.9% (14 studies, 2595 patients) [26], recent studies from the U.S. reveal higher estimates ranging between 40.0-67.5% in cohorts ranging from 12-1059 patients [27-30]. In this cohort, AST and ALT elevations were observed at admission in 66.9% and 41.6% of patients, respectively, and during hospitalization in 83.4% and 61.6% of patients, respectively. Although differences in baseline risk factors (e.g. fatty liver, alcohol, medications) and hospital management (e.g. COVID-19 treatment) may potentially account for some of this disparity, future studies are needed to clarify the extent to which such factors account for these differences. Second, the current study is consistent with prior observations that the pattern of liver injury is predominantly hepatocellular rather than cholestatic, although our study suggests that elevations in TBIL and ALP may be more common than previously reported. The ACE2 receptor is much more heavily expressed in cholangiocytes than in hepatocytes [31], so our findings may therefore suggest that the most common mechanism of liver damage is not due to a direct cytopathic effect of the SARS-CoV-2 virus. Third, we found that abnormal liver tests are usually minimally elevated (1-2x ULN), although more severe hepatitis (2-5x or >5x) may be observed. A previous study reported that 11.1% and 9.2% of AST and ALT elevations, respectively, were beyond 2x ULN at the time of hospital admission [16]. In contrast, our report reveals higher rates of abnormal liver transaminases >2x ULN at admission (36.3% AST, 36.5% ALT) and peak hospitalization (55.2% AST, 58.4% ALT), and >5x ULN at peak hospitalization (55.2% AST, 58.4% ALT), signaling that severe hepatitis is more common than previously described. Fourth, abnormal liver tests are pre-existing in a significant proportion of patients prior to hospitalization for COVID-19, particularly among patients with abnormal liver tests at hospital admission. We are not aware of previous U.S. studies that report pre hospitalization liver tests. Fifth, this study reveals an association between medications used in the treatment of COVID-19 and abnormal liver transaminases during hospitalization, with the strongest relationship observed with tocilizumab. The use of pharmacotherapy for COVID-19 may represent a surrogate for disease severity and therefore this association may be confounded by indication, although a contribution of drug-induced liver injury cannot be excluded. Finally, abnormal liver tests during hospitalization are associated with worse outcomes in COVID-19 patients, with the strongest observed between peak liver tests (AST, ALT, TBIL, ALP, albumin) and ICU admission/mechanical ventilation, as well as peak liver tests (AST, TBIL) and death.
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