Abstract
Abstract
Objective
Several studies have reported on liver injury during COVID-19. However, the definition and timing of liver injury is different among the published articles. The aim of the present study is to evaluate whether COVID-19 related liver injury at the time of first presentation is associated with the course of the disease.
Methods
We conducted a single center retrospective study at Amphia Hospital in Breda, The Netherlands, from February 1 through April 30, 2020. Patients with reverse transcription polymerase chain reaction confirmed COVID-19 were included. We excluded patients with known chronic liver disease, harmful alcohol consumption or patients on certain antibiotics prior to admission. The clinical characteristics and outcomes of patients with and without COVID-19 related liver injury were compared. Liver injury was defined as elevated alanine aminotransferase and/or alkaline phosphatase at the time when the first positive COVID-19 sample was obtained.
Results
We included 382 patients with COVID-19 infection. The incidence of liver injury was 41.6% (n = 159). Being female was associated with liver injury (p < .05). Liver injury was not associated with a more severe course of the disease in terms of hospitalization, length of hospital stay, intensive care unit admission and mortality.
Conclusion
COVID-19 related liver injury at the time of diagnosis of COVID-19 does not seem to be associated with a more severe course of the disease in our hospital.
Introduction
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a novel RNA betacoronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first identified in Wuhan, China and has evolved to a global pandemic [1]. The infection is mainly characterized by non-specific symptoms as fever, malaise, dry cough and dyspnea [2–4]. Laboratory findings typically include lymphocytopenia and elevated levels of C-reactive protein and lactate dehydrogenase [2,5]. Radiologic features consist of atypical pneumonia with bilateral and peripheral distribution [2]. The clinical spectrum of COVID-19 varies from asymptomatic patients with good prognosis to life-threatening conditions such as fulminant viral pneumonia, acute respiratory failure, acute respiratory distress syndrome and even death [2,3].
It has been recognized that SARS-CoV-2 is mainly targeting angiotensin converting enzyme 2 (ACE2) as viral entry receptor [6,7]. Studies indicate a prevalent expression of ACE2 receptor in alveolar epithelial cells, making the lungs the primary affected organ. ACE2 is also expressed in bile duct epithelial cells and in lesser extent in hepatocytes [8]. This suggests that SARS-CoV-2 might have a possible direct effect on liver tissue resulting in liver injury [3,5,9–16]. However, there is no report of detected viral inclusions in liver biopsies or autopsy in patients with COVID-19 [17]. Potential secondary mechanisms of liver injury in COVID-19 might be drug-induced liver injury, inflammation-mediated liver tissue damage or reperfusion injury due to hypoxia [3–5,9–16,18].
To date, several studies have reported on liver injury during COVID-19 infection [2,4,12,15,16,18–20]. All these studies have a retrospective, observational study design. The reported incidence of liver injury varies from 2.5% to 61.5%, mainly defined as elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels [2–4,12–14,19,20]. Levels of alkaline phosphatase (ALP) and gamma-glutamyl tranferase are not reported in most studies [3]. A prevailing majority of the affected patients have only transient and mild to moderate elevations of AST and ALT levels [3,4,9,11,12,15,16,18,19]. The proportion of infected men with elevated AST and ALT levels appears to be higher compared to women [4,9,16,19,20]. Some articles reported higher AST and ALT levels in severe COVID-19 cases and suggest that liver injury is more prevalent in severe cases [2,3,5,13–15,18,19]. Various studies documented the highest AST and ALT levels at any time during disease progression [15,18,19]. Furthermore, previous studies included patients with pre-existing liver disease or did not mention alcohol consumption [4,13,15,16,18,20]. Hence, liver injury in these studies might be caused by ischemia in severe cases, aggravation of pre-existing liver disease or administered drugs during hospital admission such as certain antibiotics, lopinavir/ritonavir or total parenteral nutrition. Therefore, the prognostic value of liver injury is still unclear.
The aim of the current study was to assess whether the presence of abnormalities in liver enzymes as a result of COVID-19, would lead to a more severe course of the disease. We examined if the admission rate to the hospital, the length of hospital stay, the ICU admission rate and mortality were significantly different between patients with and without liver injury. To increase the likelihood that liver injury, defined as elevated liver enzymes, was due to the virus itself or the virus-induced immune reaction, we evaluated the presence of liver injury in COVID-19 patients at the time when the first positive COVID-19 sample was obtained. The study has been performed in a large general teaching hospital in the Netherlands in the early stage of the pandemic.
Methods
We conducted a single center retrospective study at Amphia Hospital in Breda, The Netherlands. Patients with confirmed COVID-19 were included from February 1 through April 30, 2020. All patients were diagnosed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal or oropharyngeal swabs, sputum or faeces specimens obtained at Emergency Department visit, during hospitalization or outside the hospital. In total 432 patients tested positive for COVID-19 infection from February 26 to April 28, 2020.
We excluded patients without any results concerning liver tests at the time when the first positive COVID-19 sample was obtained. Furthermore, we excluded patients with documented chronic liver disease such as cirrhosis or diffuse liver metastasis. Harmful alcohol consumption was another exclusion criterion. Harmful alcohol consumption was defined as 14 drinks or more per week for women and 21 drinks or more per week for men. Moreover, we excluded patients on possible hepatotoxic treatment prior to RT-PCR confirmed COVID-19 such as amoxicillin-clavulate. However, this concerns a small number of patients, since there is a relatively high treshold in the Netherlands to prescribe antibiotics. The study was approved by the Medical Ethics Comittee of the Amphia Hospital.
Data collection was obtained at time of admission from the Emergency Department visit and during hospital admission from patients’ electronic medical records. Clinical data included age, gender, body mass index, alcohol consumption, prior liver disease, medication and laboratory findings. Furthermore, we collected data regarding hospital admission, the length of hospital stay, ICU-admission and mortality. Follow up ended on May 31, 2020.
We compared the clinical characteristics and outcomes of patients with COVID-19 related liver injury and without COVID-19 related liver injury. Liver injury was defined as elevated levels of ALT and/or alkaline phosphatase (ALP) at the time when the first positive COVID-19 sample was obtained. The upper limit of normal (ULN) for elevated ALT was defined as 34 U/L for women and 45 U/L for men. The cut-off value for elevated ALP is set at < 98 U/L for women and < 115 U/L for men.
During the course of our study there was no specific treatment available for COVID-19. Treatment consisted of patient isolation and supportive care including intravenous fluids and oxygen therapy in case of hypoxemia. Furthermore, antibiotics and other drugs, mainly chloroquine, were prescribed according to the Dutch SWAB-guideline in combination with the physicians’ assessment [21]. SWAB (Stichting Werkgroep AntibioticaBeleid) is the Dutch Working Party on Antibiotic Policy. This guideline was regularly updated and included the off-label use of some drugs for patients with COVID-19 who were not enrolled in clinical trials.
The primary end points were defined as hospital discharge, ICU admission or death, whichever comes first.
Categorical variables were described as frequency and percentages. Continuous variables were described using mean values when the data was normally distributed. We compared the clinical characteristics and outcomes of patients with and without liver injury using Pearson’s chi-squared test for categorical independent variables and simple logistic regression for continuous independent variables. All statistical analysis were performed using STATA version 15.0 software. A p value of < .05 was considered statistically significant.
Results
A total of 382 patients with RT-PCR confirmed COVID-19 were included for analysis from February 26 to April 28, 2020. The mean age at the time of diagnosis was 68 years (range 28 to 95 years) (Table 1). Most of the included patients were males (n = 242;63.3%). The mean BMI was 28.0 kg/m2 in our sample (range 16.6 to 53.6 kg/m2). The incidence of elevated total bilirubin (> 20 mg/dL) was 3.7% (n = 14).
Table 1. Clinical charecteristics of 382 patients with COVID-19 at first presentation.
The incidence of liver injury was 41.6% (n = 159) at the time when the first COVID-19 positive sample was obtained (Table 1). In total 86.1% of the confirmed COVID-19 patients were hospitalized (Table 2). The mean length of hospital stay was 22.5 days (range 1–75 days). The proportion of patients admitted to the ICU during the illnesswas 22.8% (n = 75). The overall all-cause mortality during the study period was 21.5% (n = 82).
Table 2. Association between liver injury at first presentation and adverse outcomes in COVID-19.
Patients were divided into two groups based on the presence of liver injury at the time when the first positive COVID-19 sample was obtained (Table 1). Females had statistically significant more liver injury compared to males (p < .05). There was no statistically significant difference in age and BMI between the group with liver injury and the group without liver injury. Liver injury was not significantly correlated with hospitalization, length of hospital stay, ICU admission or increased mortality (p > .05) (Table 2). Overall mortality was significantly associated with age of 70 years and above (n = 70;35.9%) and being male (n = 60;24.8%) (Table 3). Morbid obesity (n = 13) was not significantly correlated with mortality. However, few patients in our sample were considered morbid obese (BMI > 40 kg/m2).
Table 3. General characteristics related to overall mortality.
The incidence of moderate liver injury, defined as ALT > 100 U/L and/or ALP > 200 U/L, was 6.5% (n = 25). A mainly cholestatic liver enzyme pattern, defined as elevated levels of ALP without elevated levels of ALT, was found in 9.2% (n = 32) of the included patients. There were too few observations with moderate or mainly cholestatic liver injury to perform a reliable statistical analysis.
Discussion
Previous studies have found a correlation between liver injury and disease severity in COVID-19 patients [3,5,13,15,16,18,19]. However, the definition and timing of liver injury is different among the published articles. In most cases liver injury was defined as elevated AST or ALT levels. Some studies defined the timing of elevated liver enzymes at first presentation, while others used elevated liver enzymes during disease progression or even peak values [3,5,13,15,16,18,19]. A study in 788 patients with RT-PCR confirmed COVID-19 which only examined ALT elevation at presentation concluded that elevated ALT levels (28.8%) did not worsen the outcomes in COVID-19, consistent with the present study [16]. Another study found a relation between peak ALT values and disease severity in COVID-19, but only in a small group of patients with ALT > 5 ULN (n = 145) [15]. The same author warns for using other markers than ALT for liver injury, since ALT is the most specific marker for liver injury [15,22]. We evaluated ALT as indicator for parenchymatous liver injury and ALP as a marker for cholestatic liver injury.
Different factors can contribute to liver injury during the course of COVID-19, especially in severe cases such as hypoxemia in patients with shock as well as the administration of certain antibiotics and other treatments [3,5,9,10,12,13,15]. For example, in the aforementioned study by Phipps et al. many patients with severe liver injury received several drugs as vasopressors and different antiviral agents like remdesevir and IL-6 inhibitors [15]. Other potential mechanisms for liver injury include direct liver tissue damage by SARS-CoV-2 infecting liver cells via the ACE2 receptor and inflammation-mediated liver injury [3,5,9,10,12,13,15]. To increase the likelihood that existing liver injury in the present study was related to the virus itself or the immune response to SARS-CoV-2, we evaluated the presence of liver injury at the time when the first positive COVID-19 sample was obtained. Furthermore, we excluded patients in which other factors could have contributed to the elevated liver enzymes levels such as harmful alcohol consumption, pre-existing liver disease and possible hepatotoxic antibiotics like amoxicillin-clavulanate.
We have included all the RT-PCR confirmed COVID-19 cases presented in the period from February 1 through April 30, 2020. We presume that our sample represents an average group of Dutch COVID-19 patients, as our hospital was located in the epicentre of the Dutch pandemic during this time period. To strengthen this assumption we evaluated the female-male ratio in our sample, the prevalence of overweight and the overall mortality in males compared to females, patients older than 70 years and patients with morbid obesity. More patients are male compared to female (63% vs. 37%) and a greater proportion is overweight (BMI > 25 kg/m2) than in the general Dutch population. Mortality was significantly associated with age of 70 years and above and being male in univariable analysis. These results are in accordance with the characteristics of COVID-19 patients reported in many studies.
In the present study the incidence of liver injury related to COVID-19 infection was 41.6%, which is similar to other studies [2–4,12–14,19,20]. The incidence of severe liver injury (ALT > 5 ULN) was 1.8% (n = 7) in our study, too few observations to base an adequate conclusion on. There was no difference in the hospitalization rate, the length of hospital stay, ICU admission rate and mortality between the group with liver injury and the group without liver injury. A prevailing majority of the patiens with liver injury had only mildly elevated liver enzymes. In line with the available empirical research, our study finds low occurence of moderate to severe liver injury. However, the consequence of liver injury related to COVID-19 infection remains unknown.
The present study has some limitations. The study focuses on one hospital and the sample size is relatively small. Furthermore, we conducted a retrospective study and some documentation was incomplete. Another limitation concerns the wide definition of liver injury. In line with several other studies we have defined liver injury as elevated liver enzymes above the upper limit of normal (ULN). Moreover, since the mean BMI of COVID-19 patients exceeds the average BMI in the general population, elevated liver enzymes could also be caused by the presence of MAFLD (metabolic associated fatty liver disease) [3,23]. Even though we could exclude pre-existing liver disease in nearly all our patients, the presence of MAFLD is often unknown. However, if MAFLD would be prevalent in the group of patients with liver injury, it does not seem to influence the severity of COVID-19 infection.
In conclusion, liver injury in patients at the time of first presentation and therefore most likely caused by the virus itself or the virus-induced immune reaction, does not indicate a higher chance of a severe course of COVID-19 in our hospital. Patients with and without liver injury at presentation had a comparable admission rate to the hospital, a comparable length of hospital stay, a comparable ICU admission rate and a comparable mortality. Although well-known risk factors as sex and age were present in our patients, further extensive prospective studies are required to validate the findings.
| All (n = 382) | Liver injury (n = 159) | No liver injury (n = 223) | p Value | |
|---|---|---|---|---|
| Mean age (yr) | 68 (28-95) | 68 | 68 | .822 |
| Male gender (%) | 63.3 (n = 242) | 36.0 (n = 87)* | 64.0 (n = 155) | |
| Female gender (%) | 36.6 (n = 140) | 51.4 (=72)* | 48.6 (n = 68) | |
| BMI (kg/m2) | 28.0 (16.6-53.6) (n = 332) | 28.2 (n = 135) | 27.9 (n = 197) | .581 |
*The difference between the proportion of females with liver injury (51.4%) compared to proportion of males with liver injury (36.0%) is statistically significant (p value .003).
| All (n = 382) | Liver injury (n = 159) | No liver injury (n = 223) | p Value | |
|---|---|---|---|---|
| Hospitalization (%) | 86.1 (n = 329) | 85.5 (n = 136) | 86.5 (n = 193) | .778 |
| Length of hospital stay (days) | 22.5 (n = 329) | 21.9 (n = 136) | 22.9 (n = 193) | .946 |
| ICU admission (%) | 19.6 (n = 75) | 22.0 (n = 35) | 17.9 (n = 40) | .323 |
| Mortality (%) | 21.5 (n = 82) | 25.2 (n = 40) | 18.8 (n = 42) | .138 |
| N | Mortality (%) | p Value | |
|---|---|---|---|
| Age ≥ 70 years | 195 | 35.9 (n = 70) | .000 |
| Male gender | 242 | 24.8 (n = 60) | .037 |
| Female gender | 140 | 15.7 (n = 22) | |
| Morbid obesity* | 13 | 30.8 (n = 4) | .40 |
*Morbid obesity was defined as BMI ≥ 40 kg/m2.
Disclosure statement
None declared.
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