key: cord-0903962-dhkvh45t
authors: Ramachandran, Preethi; Perisetti, Abhilash; Gajendran, Mahesh; Chakraborti, Abhishek; Narh, Joshua Tetteh; Goyal, Hemant
title: Increased serum aminotransferase activity and clinical outcomes in Coronavirus disease 2019
date: 2020-06-30
journal: J Clin Exp Hepatol
DOI: 10.1016/j.jceh.2020.06.009
sha: 88a7050abf4d38c033289510e808c164bdfe2910
doc_id: 903962
cord_uid: dhkvh45t

OBJECTIVE: Elevation of hepatic aminotransferases (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) is commonly noted among COVID-19 patients. It is unclear if they can predict the clinical outcomes among hospitalized COVID-19 patients. We aim to assess if elevations in AST/ALT were associated with poor outcomes in hospitalized COVID-19 patients. METHODS: We retrospectively evaluated hospitalized COVID-19 patients with clinically significant elevated aminotransferases (defined as >2 times upper limit of normal) and compared them with COVID-19 patients without an elevation in aminotransferases. RESULTS: The prevalence of elevation in AST/ALT was found to be 13.7% (20/145). The two groups were similar in baseline demographics, comorbidities, and the majority of laboratory tests. There was no difference in the mortality (50% vs. 36.8%, P=0.32) and median hospital stay (7 days vs. 7 days, P=0.78). However, there was a statistically significant increase in the rates of mechanical ventilation among elevated aminotransferases group compared to individuals without elevation (50% vs. 24%, P= 0.028). However, this difference was not observed after adjusting for inflammatory markers such as ferritin, lactate dehydrogenase (LDH), and lactic acid levels. CONCLUSION: Elevated aminotransferases among hospitalized COVID-19 patients is associated with higher rates of mechanical ventilation, but did not achieve statistical significance after controlling for inflammatory markers. Also, patients with elevated aminotransferases did not have higher rates of mortality or prolonged length of stay.

The Coronavirus Disease 2019 is caused by novel severe acute respiratory syndrome corona virus-2 (SARS-CoV-2). It started as a cluster of pneumonia cases in Wuhan, China, and subsequently spread to the rest of the world (1) . During the initial outbreak of COVID-19, respiratory manifestations were the primary symptoms at the time of presentation. As more data emerged, gastrointestinal (GI) and hepatic involvements were increasingly recognized as important manifestations of COVID-19

patients (1) (2) (3) (4) (5) .

SARS-CoV-2 binds to its functional receptor-angiotensin-converting enzyme 2 (ACE-2) and gets internalized into the target cells (6) . ACE-2 receptor levels are highly expressed in the small intestine (including terminal ileum). It could explain the pathogenesis of GI manifestations such as nausea, vomiting, and diarrhea. Moreover, ACE-2 receptors are also expressed in cholangiocytes and hepatocytes, indicating that SARS-CoV-2 might directly bind to these cells resulting in hepatic dysfunction (7, 8) . Patients with preexisting liver diseases are at increased risk of COVID-19, possibly because of their immunocompromised status, but it is unclear if these individuals are at increased risk of mortality too (9) .

Elevated aminotransferases are commonly identified in COVID- 19 patients. The precise definition of elevated aminotransferases remains unclear as studies have used variable levels of AST/ALT to define liver injury (5, (10) (11) (12) . It could explain the differences in reported prevalence of deranged liver chemistries in patients with COVID-19 (ranging from 14% to 53%) (13) . Additionally, aminotransferases levels at presentation may differ from levels during the course of the disease. Though the minimal rise in aminotransferases is expected primarily because of sepsis, clinically significant elevation of at least twice the upper limit of normal (ULN) levels is crucial to recognize (14) . Furthermore, it remains to be studied if such significantly elevated liver biochemistries predict outcomes in COVID-19 patients.

Due to these gaps in current knowledge, we aim to measure the prevalence of clinically significant (twice the ULN) elevation of aminotransferase levels in hospitalized COVID-19 patients. We also assessed if this elevation is associated with poor outcomes during hospitalization when compared to the COVID-19 patients without significantly elevated aminotransferases.

It is a retrospective study from a single tertiary care academic medical center in New York, which is profoundly affected during the pandemic. This study has been approved by the institutional review board. All consecutive adult patients admitted to the Brookdale University Hospital and Medical Center with confirmed COVID-19 from March 18, 2020, to March 31, 2020, were analyzed. Inclusion criteria were all hospitalized patients with a positive nasopharyngeal swab for SARS-CoV-2, adults age 18 years or older. Exclusion criteria were-individuals who were not hospitalized or treated on an ambulatory basis, pregnancy, and unavailability of nasopharyngeal testing or laboratory data.

Data related to patient characteristics such as presenting symptoms, comorbidities, home medications, and initial laboratory tests were obtained. Demographic variables such as age, sex, race, smoking status, median body mass index (BMI) were recorded. Multiple comorbid conditions such as a history of hypertension, dyslipidemia, coronary artery disease (CAD), diabetes (DM), history of any cancer, chronic liver disease, chronic obstructive pulmonary disease (COPD), and asthma were noted. Respiratory symptoms, such as cough, fever, dyspnea, fatigue, and myalgia, were noted. Medication history of use of angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin receptor blocker (ARB), non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or statin use were collected. Furthermore, laboratory data such as median hemoglobin level, white blood cell count (WBC), lymphocyte count, platelet count, ferritin, C-reactive protein (CRP), lactate and lactate dehydrogenase (LDH) were obtained.

In our study, a significant elevation of aminotransferases was defined as two times elevation of either ALT (normal 21-72 international units per liter [IU/L]) or AST (normal 17-59 IU/L) or both from the upper normal limit (14) . Based on these criteria at presentation, the study cohort was stratified into two groups, COVID-19 patients with elevated aminotransferases (cases) and COVID-19 patients without elevated aminotransferases (controls).

The primary outcome in this study is hospital mortality from any cause, and the secondary outcomes are mechanical ventilation and the total length of stay (LOS) in the hospital. The patients who required mechanical ventilation or died in the hospital were considered to have severe COVID-19 in our study.

Statistical analysis was performed using IBM SPSS software version 26 (SPSS Inc, Armonk, NY).

Descriptive summary statistics are presented as median with interquartile range (IQR) for the continuous variables, since most of the variables are non-normally distributed, and as frequencies with percentages for categorical variables. Categorical and continuous variables were tested for statistical significance using chi-square tests and non-parametric tests, respectively. Multivariate logistic regression analysis was done for the primary dichotomous outcome variable to adjust for confounding variables. Univariate predictor variables with P < 0.05 were included in the multivariate analysis. Table 1 outlines the baseline demographics and comorbidities between the two groups. Among cases, the median age was 59.5 years (IQR 46 -70.8 years) compared to 63 years (IQR 53.5 -74 years) in controls (P=0.88). The predominant population in our study, were African Americans, consisting of 80% of cases and 74% of controls. The median BMI was higher in cases when compared with controls (32.3 vs. 28.3, P=0.02). Comorbidities such as hypertension, dyslipidemia, COPD, asthma, CAD, DM, and cancer were similarly distributed between both groups ( Table 1) . None of the patients in either groups had a documented history of chronic liver disease including alcohol liver disease and non-alcoholic steatohepatitis. The utilization of home medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and statins were similar between the two groups. Table 2 outlines the laboratory values between the two groups. Other liver chemistries as such as albumin, international normalized ratio (INR), total bilirubin, alkaline phosphatase levels did not differ among the two groups. Median hemoglobin, WBC, lymphocyte count, and platelet counts were noted with no statistical difference between the two groups. The Median ferritin level was 1680 ng/ml in cases (IQR 517.8 -3037.5 ng/ml) and 400 ng/ml in the controls (IQR 145 -896 ng/ml), but was not statistically significant (P=0.11). Median lactic acid and LDH levels were significantly higher in the cases, as noted in table 2. However, D-dimer, creatine phosphokinase (CPK), CRP were similar in both groups.

The outcomes of the study are outlined in Table 3 . There were no statistically significant differences in the mortality rates between the cases and controls (50% vs. 36.8%, P=0.32). There was a statistically significant increase in rates of mechanical ventilation among elevated aminotransferases group when compared with the control group (50% vs. 24%, P= 0.028). There was no difference found in other 

Based on our study, 13.7% of patients admitted for COVID-19 had significantly elevated aminotransferases at presentation. Elevated aminotransferases were associated with an increased rate of mechanical ventilation, but did not achieve statistical significance after controlling for inflammatory markers. However, there was no increase in the mortality rate or length of stay among patients with elevated aminotransferases.

Our study findings are similar to prior studies with abnormal liver tests. However, the prevalence of abnormal aminotransferases was found to be a lower range 1, 8, 10, 11, 15, 16, 17 which could probably be due to strict criteria of inclusion of patients with clinically significant aminotransferase elevation (twice the ULN). A recent meta-analysis reported that 15% of the patients with COVID-19 had abnormal aminotransferases, and 16.7% had abnormal bilirubin, both of which are defined as any value above the upper limit of normal (18) . Also, the aminotransferases were significantly higher in COVID-19 patients with the severe disease when compared with non-severe disease (10, 19, 20) . In a study by Cholankeril (1). A retrospective study of 148 patients at Shanghai Health center, China, showed that AST was elevated in 22% and ALT in 18% of cases (21) . In this study, authors noted that 45 patients with normal liver tests on admission developed abnormal tests at a median of 7 days after admission, indicating that multiple interventions, medications, and hemodynamic changes could contribute to these findings.

It is unclear if abnormal liver enzymes could predict severe disease and poor outcomes in COVID-19 patients. In a study by Hajifathalian et al., liver injury at presentation was associated with a 2.3 times higher risk for ICU admission and death (17) . In a study, Cai and colleagues, significantly elevated (defined as three times the ULN) AST and ALT levels at admission were associated with higher odds of progressing to severe disease (12) . Xie et al. reported that patients with elevated liver enzymes had longer LOS (22) . Also, the extent of pulmonary lesions on CT scan was a predictor of liver function abnormality in the same study (20) .

Similarly, Fan et al. noted that patients with abnormal liver function tests had longer LOS (21) . It is essential to recognize that patients in abnormal liver function groups also had higher levels of procalcitonin, CRP, and LDH, which could indicate that these patients were sicker at the time of admission. In our study, there was no increase in mortality or length of stay in patients with elevated aminotransferases. However, we found that the rate of mechanical ventilation was significantly higher in patients with elevated aminotransferases, but the statistical significance was lost when adjusted for confounding variables.

None of the studies have reported a detailed workup of abnormal liver tests in the setting of COVID-19.

Furthermore, the mechanism of liver involvement in COVID-19 is unclear, although various mechanisms have been proposed. ACE-2 is expressed in biliary epithelium and hepatocytes. Biliary epithelial ACE-2 expression can be as high as twenty times that of hepatocytes (15) . This could expose hepatic and biliary epithelium to direct viral entry with ACE-2 receptors. Other possible mechanisms include SARS-CoV-2induced direct hepatoxicity, immune-mediated damage in the setting of excess cytokine release (23) .

Drug-induced liver injury and reactivation of undiagnosed pre-existing liver disease have also been thought to be the possible mechanisms (7, 24) . Histologically, reports of direct viral cytotoxicity (such as microvesicular steatosis, mild lobular, and portal activity) and drug-induced liver injury have been noted (11, 25) . In our study population, we did not find any differences in use of home medications that can cause liver injury nor increased frequency of chronic liver disease. We observed that the patients with elevated liver enzyme groups had higher inflammatory markers (such as ferritin and LDH), which could indicate a higher inflammatory burden in these patients. However, we did not have the data to report the trends of the aminotransferases and the inflammatory markers through the hospital course.

The main strength of this study is the inclusion of only clinically significant elevation aminotransferases levels (two times the ULN). Additionally, we included data on multiple comorbidities, including medications such as NSAIDs, and ACEI/ARB. Multivariate analyses for potential confounders were performed. However, some of the limitations are worth being noted. It is a single-center retrospective study which could introduce bias and limit its generalizability. Even though none of the patients in the study population reported a history of chronic liver disease, we did not have previous records to validate this. We did not perform a trend analysis of the liver enzymes and the inflammatory markers to see if they correlate. Finally, owing to the small sample size of the current study, especially in the elevated transaminases group, there is a possibility of type II error.

Abnormal liver enzymes are commonly encountered in hospitalized COVID-19 patients. The results of our study show that clinically significant elevation of aminotransferases (2 X ULN) was noted in 13.7% of hospitalized COVID-19 patients. Elevated aminotransferases were associated with an increased rate of mechanical ventilation on univariate analysis, but was not statistically significant when adjusted for confounders. Aminotransferase elevation was not associated with increased mortality nor hospital LOS.

Further, more extensive prospective studies are needed to evaluate if elevations in aminotransferase could predict the clinical outcomes in COVID-19 patients. 

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