Accepted Article

DR. PATRICIA PRINGLE BLOOM (Orcid ID : 0000-0003-3188-7188)

Article type : Original

Liver Biochemistries in Hospitalized Patients With COVID-19

Patricia P. Bloom,1,2 Eric A. Meyerowitz,2,3 Zoe Reinus,1 Michael Daidone,1 Jenna Gustafson,1 Arthur
Y. Kim,2,3 Esperance Schaefer,1,2 and Raymond T. Chung1,2

From the 1Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital,

Boston, MA; 2Department of Medicine, Harvard Medical School, Boston, MA; 3Division of
Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, MA.

ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:

Patricia P. Bloom, M.D.
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital
55 Fruit Street, Warren 10
Boston, MA 02114
E-mail: ppbloom@partners.org
Tel.: +1-617-726-5925
or
Esperance Schaefer, M.D.
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital
55 Fruit Street, Warren 10
Boston, MA 02114
E-mail: eschaefer@mgh.harvard.edu
Tel.: +1-617-726-5925

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/HEP.31326
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 or
Accepted Article
Raymond T. Chung, M.D.
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital
55 Fruit Street, Warren 10
Boston, MA 02114
E-mail: chung.raymond@mgh.harvard.edu
Tel.: +1-617-726-5925

Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine
aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase;
COVID-19, coronavirus disease 2019; CTCAE, Common Terminology Criteria for Adverse Events;
ESR, erythrocyte sedimentation rate; ICU, intensive care unit; MGH, Massachusetts General
Hospital; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Financial Support: Dr. Bloom is a recipient of an American Association for the Study of Liver
Diseases (AASLD) Advanced Transplant Hepatology Award. Dr. Chung is supported by the
Massachusetts General Hospital (MGH) Research Scholars Program.

Potential conflict of interest: Nothing to report.

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 Abstract
Accepted Article
Coronavirus disease 2019 (COVID-19) leads to elevated liver biochemistries in approximately half of
patients on presentation. To date, data are limited regarding the trend of liver biochemistries over the
course of illness. We aimed to evaluate the trend, etiology, and outcomes associated with liver
biochemistries in COVID-19. A total of 60 patients with COVID-19 were admitted between March 21
and March 28, 2020. Mean age was 57 years, 65% were male and 28% were Hispanic. At study
conclusion, 6 patients were deceased, 28 discharged, and 26 remained admitted. Patients who
remained admitted were followed for median 12 days. Of 60 patients, 41 (69%) had at least one
abnormal liver biochemistry on admission. Median aspartate aminotransferase (AST) was higher than
alanine aminotransferase (ALT) at admission (46 vs. 30 U/L) and during the hospital course.
Aminotransferases rose above normal in 54 (93%) patients, while alkaline phosphatase and total
bilirubin elevations were rare. Ten (17%) patients developed aminotransferases more than 5 times the
upper limit of normal. AST highly correlated with ALT throughout the illness course (r = 0.97; P <
0.0001), whereas correlations with markers of muscle injury and inflammation were weak. Statin use
was common prior to (40%) and during admission (80%) at our center, with no difference in peak
liver biochemistries between users and non-users. No demographic or comorbid illness was associated
with liver injury. Admission AST (69 vs. 49; P < 0.05), peak AST (364 vs. 77; P = 0.003), and peak
ALT (220 vs. 52; P = 0.002) were higher in intubated patients. Conclusion: AST-dominant
aminotransferase elevation is common in COVID-19, mirrors disease severity, and appears to reflect
true hepatic injury.

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 Coronavirus disease 2019 (COVID-19) leads to elevated liver biochemistries in 15% to 53% of
Accepted Article
patients.(1-7) The profile of admission biochemistries is most frequently an aspartate aminotransferase
(AST) or alanine aminotransferase (ALT) elevation, with alkaline phosphatase or total bilirubin
elevations more rarely reported.(8) Severe cases of COVID-19 have higher liver biochemistries on
admission.(8) There have been only two case reports of severe liver injury in the context of COVID-
19.(9,10) Although admission liver biochemistries have been reported in several case series, few reports
have described the trend in liver biochemistries over the course of illness.

The cause of elevated liver biochemistries in COVID-19 remains unclear. Postmortem liver biopsy of
one patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) found
moderate microvascular steatosis and mild lobular and portal activity.(11) Whether those changes can
be attributed to direct viral cytopathic effect, cytokine release associated with COVID-19, ischemia, a
preexisting condition, or the result of some other cause, such as drug-induced liver injury, remains
unclear. To further complicate the picture, myositis from COVID-19 could independently lead to AST
elevation.(12)

In our cohort, several experimental therapeutics were applied, both within and outside the bounds of
formal clinical trials. These medications included hydroxychloroquine, remdesivir, and 3-hydroxy-3-
methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). Although there are currently
no proven or approved treatments for COVID-19 and clinical data about statin use in this disease are
lacking, statins were recommended at our institution for some patients for several reasons: (1) Statins
may protect against the potentially severe cardiac complications of COVID-19; (2) they may enhance
innate immune response to certain viruses (including the SARS-like coronaviruses); and (3) they have
been studied and are safe in critical illnesses and acute respiratory distress syndrome (ARDS).(13-16)
There are no published reports detailing the impact of statins on liver biochemistries in COVID-19.

In this study, we sought to clarify the trend of liver biochemistries during the illness course of
COVID-19 in hospitalized patients. We followed the first cohort of patients admitted to our center
with moderate to severe COVID-19 to evaluate the trend of their liver biochemistries, correlation of

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 liver biochemistries with other illness biomarkers and medications, and association of liver
Accepted Article
biochemistries with clinical outcomes.

Methods
Adults admitted to Massachusetts General Hospital (MGH) with a positive SARS-CoV-2 real-time
polymerase chain reaction (RT-PCR) from Saturday, March 21, 2020, through Saturday, March 28,
2020, were followed by chart review until Friday, April 3, 2020. This study was deemed exempt by
our institutional review board.

Cohort
The diagnosis of COVID-19 was made by at least one positive SARS-CoV-2 RT-PCR test performed
on nasopharyngeal swab samples. This assay was developed at MGH and authorized by the Food and
Drug Administration (FDA) under an emergency use authorization.

In accordance with our institutional clinical guidance, patients with COVID-19 were continued on a
statin if already prescribed. Medical teams were asked to consider starting atorvastatin 40 mg daily
unless there was a contraindication, such as creatine kinase greater than 500 U/L or ALT greater than
3 times the upper limit of normal. Based on our internal guidance at the time, patients with risk factors
for moderate or severe COVID-19, including at least one epidemiological and one vital sign or
laboratory value risk factor for severe disease (Supporting Table S1), were also initiated on
hydroxychloroquine for 5 days. Patients at this time were additionally considered for enrollment into
a blinded, placebo-controlled trial of remdesivir, an inhibitor of viral ribonucleic acid (RNA)-
dependent RNA polymerase.

The first 50 patients were included in the cohort consecutively. The subsequent 10 patients were
included consecutively but only those who had not been placed on statin therapy within the first 48
hours of admission. This change in cohort selection was made in an attempt to include more patients
off statin therapy.

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 Data Collection
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Chart review was performed to obtain baseline demographics, including age, sex, and prior history of
coronary artery disease, diabetes, obesity, and liver disease. Admission human immunodeficiency
virus (HIV) and viral hepatitis testing was performed in nearly all patients with COVID-19.
Admission and daily values of liver biochemistries, albumin, creatine kinase, C-reactive protein,
erythrocyte sedimentation rate (ESR), lactate dehydrogenase, and ferritin were obtained. The
administration of potentially hepatotoxic medications, including acetaminophen, remdesivir,
tocilizumab, statins, and hydroxychloroquine, was captured. Finally, clinical outcomes, including
intubation, intensive care unit (ICU) admission, death, and length of stay, were recorded.

Grade of hepatocellular liver injury was tabulated daily based on the Common Terminology Criteria
for Adverse Events (CTCAE) version 5.0 system.(17) (Supporting Table S2) The grades from 0 to 4
were based on multiples of gender-specific upper limits of normal (e.g., grade 1 = ALT or AST 1-3
times the upper limit of normal).

Statistical Analysis
Descriptive statistics were summarized using a mean and standard deviation (continuously measured)
or presented as proportions (categorical). The primary aim of our study was to describe the pattern of
liver biochemistries in patients admitted with COVID-19 over the course of their illness. These trends
were depicted with median daily values of liver biochemistries, including by key subgroups.

A secondary aim of our study was to explore associations of elevated liver biochemistries with other
markers of muscle injury and inflammation. At our institution, the reference ranges for AST, ALT,
alkaline phosphatase, creatine kinase, ESR, and ferritin vary by gender. A Pearson correlation
coefficient was performed for each comparison of gender-normalized laboratory values. Analyses
examining correlation of serologic parameters were adjusted for multiple comparisons using a
Bonferroni correction, and P < 0.01 was considered significant for those tests.

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 Another aim was to explore the impact of medications, including statins, on liver biochemistries. A
Accepted Article
parametric t test or Fisher’s exact test was used to compare variables of interest between statin use
groups.

Finally, we aimed to assess the of ability of admission liver biochemistries to predict clinical
outcomes. A parametric t test or Fisher’s exact test was used to compare variables of interest between
binary outcomes. Univariate logistic regression was also used. All data were analyzed with SAS
version 9.4 (Cary, NC).

Results
A total of 60 patients with COVID-19 were admitted from March 21 through March 28, 2020, and
followed through April 3, 2020. Of these 60 patients, 4 (7%) had a prior diagnosis of chronic liver
disease, 48 (80%) were overweight or obese, and 41 (69%) had at least one abnormal liver
biochemistry on admission (Table 1). Hepatitis B and C viral testing was negative in 46 (77%) and 44
(73%) patients, respectively; positive in none; and not tested in the remainder. Median length of stay
at the end of the study period in the entire cohort was 9 days (range: 1-20 days) and in the sub-group
who remained admitted was 12 days (range 6 to 20 days).

Pattern of Liver Biochemistries Over the Course of Illness

Median AST was higher than ALT at admission (46 vs. 30 U/L), and AST remained greater than ALT
for most of the hospital course (Fig. 1). Aminotransferases rose above the upper limit of normal in 54
(93%) patients, whereas alkaline phosphatase and total bilirubin levels were normal and stable in the
majority of patients (Supporting Fig. S1). Alkaline phosphatase and total bilirubin increased beyond 2
times the upper limit of normal in only 3 (5%) and 4 (7%) individuals, respectively.

Given that abnormal liver biochemistries were primarily limited to aminotransferases, patients were
stratified by peak grade of hepatocellular liver injury. Of 59 patients, 4 (7%) peaked at grade 0 (male:
AST <40 U/L or ALT <55 U/L; female: AST <32 U/L or ALT <33 U/L); 32 (54%) at grade 1 (male:
AST 41-120 U/L or ALT 34-99 U/L; female: AST 33-96 U/L or ALT 34-99 U/L); 13 (22%) at grade

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 2 (male: AST 121-200 U/L or ALT 166-275 U/L; female: AST 97-160 U/L or ALT 100-165 U/L);
Accepted Article
and 10 (17%) at grade 3-4 liver injury (male: AST >201 U/L or ALT >276 U/L; female: AST >161
U/L or ALT >166 U/L).

AST was highly correlated with ALT on admission (r = 0.91; P < 0.0001) as well as every subsequent
day of admission (Supporting Fig. S2). In addition, peak AST correlated with peak ALT during
hospitalization (r = 0.97; P < 0.0001).

In the 10 patients who experienced grade 3-4 liver injury, AST was greater than ALT on 68% of
patient-days (Supporting Fig. S3). In 8 of 10 (80%) patients with grade 3-4 liver injury, the AST or
ALT began to rise within the first 4 days of admission. In the first 4 days, 5/10 (50%) were admitted
to the ICU, 5/10 (50%) were intubated, 4/10 (40%) were enrolled in a placebo-controlled remdesivir
trial, 6/10 (60%) were taking a statin, 9/10 (90%) received acetaminophen, and none were given
tocilizumab.

Association of AST With Markers of Muscle Injury

Two markers of muscle injury were examined: creatine kinase and lactate dehydrogenase. Creatine
kinase is found in muscle, and lactate dehydrogenase is found in many body tissues, including muscle
and liver. On admission, AST correlated with creatine kinase (r = 0.74; P < 0.0001) and lactate
dehydrogenase (r = 0.55; P = 0.002). However, this correlation diminished on subsequent days (Fig.
2), and peak AST values did not correlate with peak creatine kinase (r = 0.03; P = 0.82) or peak
lactate dehydrogenase (r = 0.23; P = 0.08) values. Across all days combined, AST had weak
correlation with creatine kinase (r = 0.31; P < 0.0001) and moderate correlation with lactate
dehydrogenase (r = 0.43; P < 0.0001). ALT weakly correlated with lactate dehydrogenase across all
days combined (r = 0.27; P < 0.0001) but did not correlate with creatine kinase (r = 0.09; P = 0.10).

Association of Liver Biochemistries With Markers of Inflammation

C-reactive protein and ESR were examined as markers of inflammation, as well as ferritin, which is
an acute-phase reactant and can be elevated in liver injury. Admission AST correlated with ferritin (r

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 = 0.41; P < 0.05) but not with C-reactive protein (r = 0.005; P = 0.98) or ESR (r = −0.03; P = 0.89).
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Correlation between AST and ESR and C-reactive protein remained weak over the course of
admission (ESR: r = 0.28, P < 0.0001; C-reactive protein: r = 0.19, P = 0.0005), whereas AST
moderately correlated with ferritin over time (r = 0.50; P < 0.0001; Fig. 3).

Association of Liver Biochemistries With Statins

Statin Use Before Admission
Statins were prescribed in 40% of our cohort before admission, and we sought to determine whether
their use had any impact on liver biochemistries during the course of illness. Admission AST, ALT,
and total bilirubin did not differ between patients who were prescribed and not prescribed statins
before admission (AST: P = 0.23; ALT: P = 0.27; total bilirubin: P = 0.68). Admission alkaline
phosphatase was higher in patients on preadmission statins; however, mean values were within the
normal range in both groups (86 vs. 66 U/L; P = 0.01). Comparing patients who were on and not on
statin therapy before admission, there was no difference in peak grade of hepatotoxicity (P = 0.52).

Statin Use During Admission

Medical teams at our institution were asked to consider initiation of statins in patients with moderate
to severe COVID-19 unless there was a contraindication, such as creatine kinase greater than 500 U/L
or ALT greater than 3 times the upper limit of normal. Even if a patient did not meet these exclusion
criteria, medical teams were not required to initiate a statin and the decision was left to their clinical
judgment. Of 60 patients with COVID-19, 48 (80%) were administered statin therapy during their
hospitalization. Of the 48 patients on statins during admission, 24 (50%) had a previous prescription
and 24 (50%) did not. Home statin use was continued for 9 (37%) patients with a prior statin
prescription; however, 15 (63%) had a change in the type or dose of statin while admitted, with
atorvastatin 40 mg daily prescribed for 14 cases. From chart review, we cannot be certain about the
rationale for these changes; however, in the majority of cases it appeared to reflect an effort to follow
institutional guidance.

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 Patients who received statins while hospitalized (n = 48) had a lower admission AST level (49 vs. 84;
Accepted Article
P = 0.005) than those who did not receive statins (n = 12). There was no difference in age (P = 0.11),
peak AST (P = 0.72), peak ALT (P = 0.35), or peak creatine kinase (P = 0.95) between statin users
and non-users. Patients who received statins during admission were more likely to be prescribed
acetaminophen (96% vs. 67%; P = 0.01) and hydroxychloroquine (81% vs. 42%; P = 0.01;
Supporting Table S3). Of note, there was no significant difference in grade of liver injury during
admission between statin users and non-users during the admission (1.4 vs. 2.0; P = 0.06).

Patients continued on a home statin (n = 24) were older (65 vs. 53 years; P = 0.01) and more likely to
have diabetes (46% vs. 8%; P = 0.008) than those who started a new statin (n = 24; Supporting Table
S3). There was no difference in peak AST (P = 0.22), peak ALT (P = 0.15), peak creatine kinase (P =
0.41), or peak grade of liver injury (P = 0.20) between the two groups. In addition, patients newly
started on a statin were just as likely to have their statin stopped for elevated liver biochemistries
(23% vs. 23%; P = 1.00).

Patients who needed to stop statin therapy due to elevated liver biochemistries had higher admission
AST (78 vs. 43; P = 0.002) and admission ALT (60 vs. 33; P = 0.001) than those able to continue
statin therapy (Supporting Table S4). Also, a larger percentage of patients who needed to stop statins
were enrolled in the placebo-controlled remdesivir trial (70% vs. 32%; P = 0.04) than patients who
were able to continue statins. In some cases, the statin was discontinued in an effort to keep liver
biochemistries within the acceptable range for trial inclusion (inclusion and exclusion criteria for the
National Institutes of Health [NIH]-sponsored remdesivir trial; Supporting Table S5). Peak AST (P =
0.72), peak ALT (P = 0.82), and peak grade of liver injury (P = 0.78) did not differ between those
enrolled and not enrolled in the remdesivir trial.

Variables Associated With Liver Injury in COVID-19

No demographic or comorbid illness was significantly associated with more severe grades of liver
injury (Table 2), including characteristics associated with severe COVID-19, such as age (P = 0.60),
gender (P = 0.73), diabetes (P = 0.10), and coronary artery disease (P = 1.00).

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Accepted Article
Association of Liver Biochemistries With COVID-19 Clinical Outcomes
At the conclusion of the study period, 28 patients were discharged, 26 patients remain admitted, 6
died, 22 required ICU admission, and 19 required intubation.

Admission AST was higher in patients requiring intubation (69 vs. 49; P < 0.05; Table 3) but did not
predict ICU admission (odds ratio [OR], 1.01 [1.00, 1.03]; P = 0.09) or intubation (OR, 1.02 [1.00,
1.03]; P = 0.06) in univariate logistic regression. Patients requiring intubation had a higher peak
hepatocellular injury grade (2.1 vs. 1.3; P = 0.0005). Length of stay also rose with increasing grade of
liver injury (P = 0.03; Supporting Fig. S4).

The patients who died were older (78 vs. 55 years; P = 0.001) than the surviving patients. The patients
who died did not have higher peak grade of liver injury (P = 0.32), admission AST (P = 0.16), peak
AST (P = 0.48), or peak ALT (P = 0.26). Admission ALT was lower in those who died (20 vs. 42; P
= 0.03). Of the 6 patients who died, none required statin cessation due to elevated liver
biochemistries.

Impact of Chronic Liver Disease

The 4 patients with preadmission liver disease diagnoses included 1 patient with alcohol-associated
cirrhosis and 3 patients with a noninvasive diagnosis of nonalcoholic fatty liver disease, often made
by imaging. These latter 3 patients had no formal preadmission fibrosis assessment. Of these 4
patients with chronic liver disease, 2 peaked at grade 1 and 2 peaked at grade 3 liver injury. One of
the 4 patients with chronic liver disease, although not cirrhosis, was admitted to the ICU, required
intubation, and died. The remaining 3 patients with liver disease did not require ICU stay or
intubation and survived to the end of the study period.

Discussion

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 In this cohort of patients admitted to an academic American medical center with COVID-19, 69% had
Accepted Article
abnormal liver biochemistries at admission and 93% developed liver biochemistries above the upper
limit of normal during hospitalization. The pattern of liver biochemistries was generally consistent
with hepatocellular injury, with an AST predominance. Nearly 1 in 5 patients developed grade 3 or 4
hepatocellular injury during their hospitalization.

This rate of abnormal liver biochemistries on admission is considerably higher than reported cohorts
in China.(1,2) This is despite a lower upper limit of normal for male AST and ALT in most Chinese
cohorts compared to ours.(3,4,8,9,18,19) Our findings are consistent with high rates of elevated admission
AST (58.4%) and ALT (39.0%) in a large New York cohort.(20) To our knowledge, ours is the first
published report to describe liver biochemistries over the course of hospitalization and in a cohort at
an American medical center. Of our cohort, 80% were overweight or obese, perhaps with
undiagnosed nonalcoholic fatty liver disease, which may explain some of the discrepancy from
Chinese cohorts. In addition, the bar for hospital admission may have differed, with sicker patients
being admitted to our institution. It has been demonstrated that patients with severe COVID-19 have
higher liver biochemistries.(8) Given the high incidence of abnormal liver biochemistries in our cohort,
we agree with the guidance from the American Association for the Study of Liver Diseases (AASLD)
that liver biochemistries should be monitored in all hospitalized patients with COVID-19.(21)

Viral hepatitis classically leads to an ALT-predominant hepatocellular injury; however, patients with
COVID-19 did not match that pattern. Given that AST is also produced in muscle and patients with
COVID-19 develop elevated markers of muscle injury, the AASLD and others have recommended
consideration of myositis or cardiac injury as contributors to the AST elevation.(12,21,22) In our cohort,
AST correlated moderately well with a marker specific to muscle injury on admission but not on
subsequent days or overall. Likewise, we hypothesized that the hepatitis in COVID-19 may be related
to the proinflammatory state associated with cytokine release. However, AST did not correlate with
markers specific to inflammation over the course of hospitalization. Instead, AST correlated very
strongly with ALT on admission and throughout the hospitalization. This suggests true hepatic injury
as the predominant source of aminotransferase elevation.

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Accepted Article
With this study, COVID-19 joins the list of other conditions associated with AST-predominant
aminotransferase elevations, including alcohol-related liver disease, ischemia, and cirrhosis. These
other conditions may provide a clue about the underlying pathophysiology of COVID-19’s impact on
the liver. It is possible that COVID-19 spurs metabolic changes such as hepatic steatosis, as was
demonstrated in a single case report of a liver biopsy from a patient with COVID-19, although it is
not clear whether these changes predated COVID-19.(11) Alternatively, abnormal coagulation markers
have been seen in COVID-19 infection, and it is possible that microthrombi lead to altered hepatic
perfusion and subsequent hepatocyte injury and AST elevation.(23,24) In light of the AST dominance,
mitochondrial injury is a possible underlying mechanism of COVID-19 liver injury. Recently
published data have identified ribosomal proteins as important host-dependency factors for SARS-
CoV-2, and thus the virus may directly cause mitochondrial injury.(25) Finally, mild AST-dominant
aminotransferase elevations have been reported in influenza, with cytokine-mediated injury or
hypoxia having been postulated as possible mechanisms.(26) Indeed, COVID-19 is characterized both
by profound hypoxia and a robust but inappropriate cytokine response, and therefore these may be
central mechanisms of hepatic injury in COVID-19 as well.(27)

There are currently no proven or approved treatments for COVID-19. Statins are being considered as
a potential component of COVID-19 therapy for several reasons. First, cardiovascular complications
have been described as a result of COVID-19, and statin therapy could potentially mitigate that
risk.(13,14) Second, there is a theoretical role for statins in modulating the innate immune response of
viral respiratory infections—in particular, by inhibiting myeloid differentiation factor 88 (MYD88)
gene induction, which may be driven by SARS-like coronaviruses and precipitate
hyperinflammation.(15,28) Finally, statin use may be associated with less severe viral pneumonia.(29,30)
In our cohort, patients were not randomly placed on statin therapy and therefore statin users were
different in many ways from non-statin users, limiting our ability to make accurate comparisons.
Despite this limitation, there was no signal of increased liver injury in patients on statin therapy,
including those newly started on statins. Prior studies have found that the risk of statin-related drug-
induced liver injury is low overall and no higher in patients with baseline abnormal liver

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 biochemistries, again suggesting that statin initiation during admission for COVID-19 may be low
Accepted Article
risk for significant hepatotoxicity.(31,32) Randomized controlled trials are being prepared to test the
safety and efficacy of statin therapy in COVID-19. Notably, randomized controlled trials have shown
the safety of statins in ARDS and a potential mortality benefit in the setting of a hyperinflammatory
subphenotype of ARDS, of which COVID-19 has some important similarities.(16,33)

Liver biochemistries were associated with disease severity and clinical outcomes. Admission AST
was higher in those requiring ICU stay and intubation but did not predict death. It should be noted,
however, that some patients remained intubated and critically ill at the end of our study period with a
median follow-up of 12 days. Degree of hepatocellular injury was associated with length of stay, ICU
admission, and intubation, but not death. This finding suggests that liver injury from COVID-19 is
associated with severe disease but is not associated with liver failure or risk of death. However, longer
follow-up in larger cohorts will be required to draw conclusions about the prognostic value of liver
biochemistries in this condition.

The results of this study must be interpreted within the context of study design. First, liver
biochemistries and other important laboratory markers were not assessed daily on every patient
because this was not required for clinical decision making. Second, given the context of numerous
simultaneous factors, including severity of viral illness, hemodynamic changes, and multiple
medications, it is challenging to tease apart the influence of medications, such as statins, on liver
biochemistries. To complicate matters, more than one-third of the cohort was enrolled in a blinded
placebo-controlled study of remdesivir, a potentially hepatotoxic antiviral medication. Given the
blinded status of that medication, we cannot control for its influence on biochemistries and outcomes.
Third, in order to present the medical community with prompt information in the setting of a rapidly
progressive pandemic, we have not been able to observe all clinical courses to completion. Future
studies will certainly be required to ascertain the potential of liver biochemistries to predict clinical
outcomes. Finally, with only a few cases of incompletely characterized chronic liver disease in this
cohort, we cannot draw conclusions about hepatic injury and other outcomes for those patients.

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 In conclusion, this study provides novel insight into the trend of liver biochemistries during COVID-
Accepted Article
19 progression. Our data suggest that aminotransferase elevations not only mirror COVID-19 severity
but also raise the possibility that the pattern of AST-dominant elevation reflects a unique virally
mediated mechanism of hepatic injury.

Acknowledgment: We thank Cheryl Nath, Meghan Lee, Ian Strohbehn, Arley Donovan, and Jasneet
Aneja, M.P.H., for their contributions to data collection.

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Accepted Article
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 Figure Legends
Accepted Article
FIG. 1. Caption: Trend of AST and ALT stratified by peak grade of liver injury
Descriptive text: Of the 60-patient cohort, 59 had liver biochemistries checked at least once and were
included in this figure. Liver injury grade is based on the CTCAE version 5.0 grading system for AST
or ALT elevation; see methods for details. AST denotes aspartate aminotransferase; ALT alanine
aminotransferase; ALP alkaline phosphatase.

FIG. 2. Caption: Trend and correlation of AST and creatine kinase over time
FIG A: Descriptive text: Mean AST and creatine kinase were divided by the gender-specific upper
limit of normal are depicted over time for all patients. Daily Pearson correlation between these two
values are depicted below the figure, along with P-value.
FIG B: Descriptive text: Mean AST and creatine kinase were divided by the gender-specific upper
limit of normal are depicted over time only for the patients with peak grade 3-4 liver injury.

FIG. 3. Caption: Correlation between AST and inflammatory markers over time.

Supporting FIG. S1. Alkaline phosphatase and total bilirubin over time.
FIG A: Descriptive text: Median alkaline phosphatase over time.
FIG B: Descriptive text: Median total bilirubin over time.

Supporting FIG. S2. Caption: Correlation between AST and ALT over time.

Supporting FIG. S3. Individual liver biochemistry trends in those with grade 3-4 injury. Descriptive
text. RDV trial refers to patients enrolled in the NIH-sponsored placebo-controlled remdesivir trial.
We remain blinded and do not know to which arm patients were randomized.

Supporting FIG. S4. Length of stay by peak grade of liver injury

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Accepted Article TABLE 1. Characteristics of Patients Admitted With COVID-19

Admission Characteristics Data (n = 60)

Age, years 57 ± 17

Sex, male 39 (65%)

Ethnicity Hispanic: 17 (28%); not Hispanic: 43 (72%)

Race Caucasian: 38 (63%); black: 2 (3%);

Asian: 2 (3%); unknown or other: 18 (30%)

Body mass index category Normal: 12 (20%); overweight: 21 (35%);

obese: 27 (45%)

Statin prior to admission 24 (40%)

Coronary artery disease 11 (18%)

Diabetes 14 (23%)

Chronic liver disease 4 (7%)

Cirrhosis 1 (2%)

AST, U/L 55 ± 37

ALT, U/L 39 ± 24

Alkaline phosphatase, U/L 75 ± 31

Total bilirubin, mg/dL 0.9 ± 2.2

Abnormal liver biochemistry† 41 (69%)

Serum albumin, g/dL 3.7 ± 0.4

Data are presented as mean ± SD unless mentioned otherwise.

†
Defined as AST, ALT, alkaline phosphatase, or total bilirubin above the upper limit of normal. In
addition, 59 patients had liver biochemistries checked on admission. For this admission characteristic
alone, the denominator was 59.

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Accepted Article TABLE 2: Factors Associated With Grade of Hepatocellular Injury
Grade 0-2 Injury Grade 3-4 Injury
Characteristics P-value
(n = 50) (n = 10)
Age, years 58 ± 17 55 ± 16 0.60
Sex, male 33 (66%) 6 (60%) 0.73
Hispanic ethnicity 14 (28%) 3 (30%) 1.00
Body mass index 30 ± 6 31 ± 4 0.82
Diabetes 14 (28%) 0 (0%) 0.10
Coronary artery disease 9 (18%) 2 (20%) 1.00
Chronic liver disease 2 (4%) 2 (20%) 0.13
Data are presented as mean ± SD unless mentioned otherwise.

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Accepted Article TABLE 3: Liver Biochemistries Associated With Intubation
Intubation (n = 19) No Intubation P-value
(n = 41)
Admission labs
AST, U/L 69 ± 39 49 ± 35 0.049
ALT, U/L 46 ± 28 36 ± 22 0.12
Alkaline phosphatase, U/L 67 ± 26 77 ± 33 0.24
Total bilirubin, mg/dL 0.7 ± 0.5 0.9 ± 2.6 0.75
Peak labs during admission
AST, U/L 364 ± 572 77 ± 54 0.003
ALT, U/L 220 ± 304 52 ± 35 0.002
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; OR, odds ratio; CI,
confidence interval.

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 Peak Liver
N Median Liver Biochemistry Over Time
Injury Grade
Accepted Article
Entire group 59 100

Levels (U/L)
80

AST/ALT
60
AST
40
ALT
20
0
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14
N 58 47 50 43 40 38 34 28 30 23 20 17 15 10

40
Grade 0 4
Levels (U/L)

30
AST/ALT

20 AST
ALT
10

0
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14
N 4 2 3 2 1 1 0 0 0 0 0 0 0 0

Grade 1 32 100
80
Levels (U/L)
AST/ALT

60
AST
40 ALT
20
0
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14
N 31 23 26 20 17 17 15 11 13 9 8 5 4 1

Grade 2 13 150
Levels (U/L)

100
AST/ALT

AST
50 ALT

0
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14
N 13 12 11 11 12 11 10 9 9 8 7 7 6 5
200
Grade 3-4 10
Levels (U/L)

150
AST/ALT

100 AST
ALT
50

0
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14
N 10 10 10 10 10 9 9 8 8 6 5 5 5 4

hep_31326_f1.eps

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 A
4.5
Lab value/upper limit of normal

Accepted Article 4

3.5

2.5
AST

2
Creatine kinase
1.5

0.5

0
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14

.74 .56 .33 .32 .44 .10 .09 -.07 -.15 .13 .33 -.07 -.02 .005
r
<.0001 .0003 .06 .06 .02 .59 .67 .74 .50 .60 .21 .79 .95 .99
P
B
12
Lab value/upper limit of normal

AST
10

Creatine kinase
8

0
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14

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hep_31326_f2.eps
 1.2
Accepted Article 1

0.8
Correlation (r) with AST

0.6

ESR
0.4
C-reactive protein
Ferritin
0.2

0
1 2 3 4 5 6 7 8 9 10 11 12 13 14

-0.2

-0.4
Day of admission

hep_31326_f3.eps

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