http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-5-interview-schaefer
the interview with the author
Abbreviations
ACE2
angiotensin‐converting enzyme 2
ALT
alanine aminotransferase
AST
aspartate aminotransferase
COVID‐19
coronavirus disease 2019
FDA
US Food and Drug Administration
GGT
gamma‐glutamyl transferase
GI
gastrointestinal
OR
odds ratio
PT
prothrombin time
SARS
severe acute respiratory syndrome
The novel coronavirus severe acute respiratory syndrome corona virus 2 (SARS‐CoV‐2)
is currently estimated to have infected more than 3 million individuals worldwide
and causes the clinical syndrome of coronavirus disease 2019 (COVID‐19). Although
the primary clinical manifestation is pulmonary disease, increasing data support the
involvement of multiple organ systems, including the gastrointestinal (GI) tract and
liver, with more than 60% of patients presenting with GI symptoms (anorexia, diarrhea,
nausea, and vomiting) and a significant proportion presenting with elevated liver
biochemistries.
1
,
2
,
3
,
4
The SARS‐CoV‐2 virus is an enveloped, single‐stranded virus, and the angiotensin‐converting
enzyme 2 (ACE2) receptor is thought to be a major receptor for the viral spike protein
and critical for infectivity.
5
,
6
The ACE2 protein is found at high levels in the colon, biliary system, and liver,
7
and RNA shedding in the GI tract is well described.
8
These data suggest that the SARS‐CoV‐2 may have tropism for the GI tract and liver,
and that these may be sites of active viral replication and either direct or indirect
tissue injury (Fig. 1).
Fig 1
SARS‐CoV‐2 and the GI tract and liver.
Liver injury in the setting of COVID‐19–related illness poses a unique challenge to
the clinician. First, there is often uncertainty whether there is preexisting undiagnosed
liver disease. Second, many of the medications used to treat moderate and severe disease
have their own profiles of liver toxicity. Finally, in the subset of patients who
experience critical illness, multiple factors may influence the trajectory of liver
injury. We summarize what is known about liver injury in COVID‐19 and provide diagnostic
clues to contributing factors to the liver biochemical profile.
Epidemiology and Clinical Associations of Liver Injury in COVID‐19
Several published studies have characterized the frequency and severity of liver biochemistry
abnormalities on presentation, and a few have determined whether these abnormalities
are associated with increased disease‐related morbidity or death, as summarized in
Table 1.
9
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10
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12
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13
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14
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16
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17
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18
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19
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20
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22
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23
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24
The largest published study to date encompassed 5700 hospitalized patients in New
York and examined admission serologies: aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) were both frequently elevated (58.4% and 39.0% of subjects,
respectively), and a separate large cohort found elevations to be more common in severe
disease.
9
Two studies suggest that a higher proportion (44%‐81%) of patients with underlying
liver disease had abnormal liver biochemistries on admission.
11
,
12
Elevations have been generally modest on admission, but available data suggest they
become more frequently (93% in one series) and more severely deranged during the course
of hospitalization.
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13
,
14
Furthermore, liver impairment at admission has not been consistently associated with
length of hospital stay,
11
,
15
but has been found to correlate with time from illness onset to admission and with
adverse outcomes.
14
,
15
Liver biochemistries do not appear to be associated with GI manifestations in COVID‐19.
2
Table 1
Frequency of Liver Biochemistry Abnormalities on Admission and Association With Outcomes
Laboratory Test
% Patients With Abnormal Value*
Association With Severe Disease
†
Association With Death
Comments
AST
16%‐58%
9
,
10
,
12
,
16
,
17
,
18
,
19
Yes
13
,
14
,
16
,
18
Yes
21
In 1 review of 12 published and unpublished reports, AST was the most frequently elevated
biochemistry, and more frequently abnormal in severe disease
22
ALT
13%‐39%
9
,
10
,
12
,
17
,
23
Yes
13
,
16
,
18
Yes
21
,
23
Risk for in‐hospital death is associated with ALT > 40 (OR: 2.87 [1.48‐5.57]; P = 0.0018)
and PT ≥ 16
23
No
20
Alkaline phosphatase
5%
12
Yes
13
TBili
11%‐23%
10
,
12
,
17
Yes
16
No
13
,
18
Albumin
38%‐98%
17
,
18
Yes
16
,
18
,
20
,
24
Yes
23
Murray lung injury score is highly correlated with albumin (r = −0.959, P < 0.001)
24
GGT
16%
12
Yes
13
Increase in GGT in one study was observed despite normal alkaline phosphatase level
12
PT
5%‐6%
17
,
23
Yes
16
Yes
23
Elevated PT on admission significantly associated with risk for death (OR: 4.62 [1.29‐16.50];
P = 0.019)
23
No
18
*
Above normal limits, as designated by study authors.
†
Abnormal laboratory value at any point in disease course. Severe disease is a composite
definition composed of author designation of “severe disease,” disease progression,
lung injury, and intensive care unit level care. Abbreviation: TBili, Total Bilirubin
John Wiley & Sons, Ltd
Patterns of Liver Injury
Aminotransferase elevation is the most common abnormality in patients presenting with
COVID‐19 (Table 1). Published reports suggest that AST is more frequently elevated
than ALT.
9
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10
,
13
,
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Elevated alkaline phosphatase is rare, and an increase in bilirubin has less commonly
been observed. However, interestingly, one report found elevated gamma‐glutamyl transferase
(GGT) levels in nearly 50% of subjects.
12
The trajectory of liver biochemistry changes during hospitalization for COVID‐19 infection
is marked by elevation in aminotransferases, with rare severe liver injury, and liver
test abnormalities are more frequent in patients with more severe COVID‐19.
12
,
14
This pattern of liver injury is unlike that commonly observed in other forms of viral
hepatitis, such as hepatitis B and C, but at least one report describes a similar
pattern during influenza A/H1N1 influenza infection.
25
,
26
In the prior severe acute respiratory syndrome (SARS) outbreak of 2003, a similar
pattern of liver injury was observed.
27
The pattern of abnormal liver biochemistries characterized by an AST level greater
than ALT, with accompanying GGT elevation, is also commonly encountered in both alcoholic
liver disease and ischemic or congestive liver injury.
28
Thus, the liver injury observed in COVID‐19 may reflect a direct viral effect, but
other potential contributors must be considered, both at the time of initial presentation
and during disease progression and management.
Potential Causes of Liver Injury in COVID‐19
Hepatic injury from SARS‐CoV2 infection is observed from the time of initial contact
with the medical system, suggesting that the primary insult is unrelated to medical
management but rather due to either direct effect of the virus or a consequence of
the systemic disease. However, the trajectory of liver injury is likely influenced
by multiple additional factors (Fig. 2).
Fig 2
Potential mechanisms of liver injury and abnormal biochemistries.
There may be a direct viral cytopathic effect, given the known presence of the ACE2
receptor in the liver.
5
,
29
In SARS infection, viral RNA was detected in liver tissue.
30
,
31
Further, recently published data suggest that mitochondrial proteins may directly
interact with the virus,
32
providing a potential mechanistic explanation for the AST‐dominant injury profile.
Alternatively, the robust inflammatory response seen in COVID‐19 may play a central
role. The immune response to SARS‐CoV‐2 is characterized by very high levels of IL‐6,
33
which has been implicated in both the inflammatory and the repair responses in liver
disease.
34
Cardiomyopathy is a well‐described consequence of COVID‐19, occurring in 33% of individuals
in one US series.
35
Thus, it is possible that cardiac dysfunction and hepatic congestion contribute to
hepatic injury in severe COVID‐19 infection. Congestive hepatopathy may occur as a
consequence of an acute cardiomyopathy, and it is commonly associated with elevations
in aminotransferases and GGT.
36
,
37
Severe ischemic hepatitis is a condition characterized by severe AST‐predominant hepatitis
38
and may be observed in critically ill patients with COVID‐19. The infrequently observed
alkaline phosphatase elevation occurs late in COVID‐19 disease progression and could
reflect the cholestasis of sepsis, critical illness,
39
or medication effect.
An increasing number of drugs are being investigated and empirically used in hospitalized
patients with COVID‐19. Many of these medications have a distinct risk, time course,
and pattern of liver injury, as summarized in Table 2.
41
Remdesivir (a nucleoside analog inhibitor of viral RNA polymerase, recently approved
for use under a US Food and Drug Administration [FDA] Emergency Use Authorization)
is experiencing growing use in COVID‐19 trials and was associated with a 23% increase
in liver enzymes in one small published report.
40
Table 2
Drugs Commonly Used in COVID‐19 and Hepatotoxicity Profile
Drug
Liver Toxicity Score
Pattern of Injury
Time Frame of Injury
Comments
Acetaminophen
A
Hepatocellular
Protracted therapy (>4 g daily): 3‐7 days
Injury due to overdose is often associated with jaundice, confusion, renal insufficiency,
and hepatic failure, at 48‐96 hours
Single overdose: 24‐72 hours
Azithromycin
A
Cholestatic > hepatocellular
Cholestatic: 1‐3 weeks
Associated with fatigue, jaundice, abdominal pain, and pruritus
Hepatocellular: 1‐3 days
Statins
A/B
Hepatocellular > cholestatic
6 months to several years
Hydroxychloroquine
C
Very rare
NR*
Case report level data
Lopinavir/ritonavir
D
Hepatocellular/cholestatic/mixed
1‐8 weeks
May exacerbate underlying chronic viral hepatitis
Remdesivir
NA**
Hepatocellular
5‐25 days
ALT elevation observed in the majority of healthy patients; FDA recommends hepatic
function testing prior to initiating, and then daily while on therapy; stop drug if
ALT > 5 times the upper limit of normal
41
a
Not reported.
b
Not applicable.
Data are adapted from LiverTox (livertox.nih.gov).
43
John Wiley & Sons, Ltd
Conclusions
There is a high prevalence of abnormal liver biochemistries on presentation in patients
with COVID‐19. In light of the risk for additional injury due to the complications
and management of moderate‐to‐severe disease, it is important to monitor hepatic enzymes
during the course of disease.
42
If biochemistries worsen during disease progression, consideration must be given to
possible contributors, including cardiac dysfunction, cytokine storm, ischemia, sepsis,
and medication effect.