Clinical Gastroenterology and Hepatology 2019;17:1201–1203

RESEARCH CORRESPONDENCE
A Multicenter Study Into Causes of Severe Acute Liver Injury
Anthony C. Breu,*,‡ Vilas R. Patwardhan,‡,§ Jennifer Nayor,‡,k Jalpan N. Ringwala,¶
Zachary G. Devore,# Rahul B. Ganatra,‡,** Kelly E. Hathorn,‡,k Laura Horton,‡,‡‡
Sentia Iriana,‡,§ and Elliot B. Tapper§§,kk,¶¶
*Veterans Affairs Boston Healthcare System, West Roxbury, Massachusetts; ‡Harvard Medical School, Boston, Massachusetts;
§
Division of Gastroenterology and Hepatology, #Department of Medicine, **Division of General Medicine and Primary Care,
Beth Israel Deaconess Medical Center, Boston, Massachusetts; kDivision of Gastroenterology and Hepatology, and
Endoscopy, ‡‡Department of Internal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; ¶Boston University
School of Medicine, Boston, Massachusetts; §§Division of Gastroenterology and Hepatology, University of Michigan, Ann
Arbor, Michigan; kkInstitute for Healthcare Policy and Innovation, Ann Arbor, Michigan; ¶¶Veterans Affairs Ann Arbor Healthcare
System, Ann Arbor, Michigan

he differential diagnosis of an increase in alanine
T aminotransferase (ALT) level and/or aspartate
aminotransferase (AST) level of 1000 IU/L often is
stated to include 3 main etiologies: ischemic hepatitis,
acute viral hepatitis (typically hepatitis A and hepatitis
B), and drug-induced (more specifically, acetamino-
phen/paracetamol) liver injury (DILI).1 Unfortunately,
there are a paucity of studies examining the most com-
mon causes of acute liver injury (ALI) and those that
have been published have been small,2 single-center,2
or examined less severe increases in ALT or AST
levels.3,4 We conducted a multicenter study of all
patients with an ALT and/or AST level 1000 IU/L.
Our study had 3 main goals: (1) to determine the
most common causes of an ALT and/or AST level
1000 IU/L, along with their relative frequencies; (2)
to determine differences in etiology based on hospital
type (liver transplant center, community hospital, Vet-
erans Affairs hospital); and (3) to confirm or disprove
the differential heuristic that ischemic hepatitis, acute
viral hepatitis, and acetaminophen toxicity are the
most common etiologies.
Methods
Study Design and Patients
To capture a diverse patient population, patients from
3 hospital settings were included: a large tertiary liver
transplant center (transplant site), a community hospital
(community site), and a Veterans Affairs hospital (VA
site). For 2 sites, all episodes with at least 1 ALT or AST
value of 1000 IU/L recorded between January 2010
and December 2015 were eligible for inclusion. For the
third site, episodes were chosen at random using a data
abstraction tool for the clinical data warehouse. Patients
who died, were transferred to a nonstudy facility, or
were discharged before evaluation of the increased ALT
and/or AST level could be performed were excluded. An
episode was defined as the 30-day period including all
ALT or AST values recorded after the initial value of
1000 IU/L.
Classification of Cause of Transaminases
Chart reviews were performed by single in-
vestigators at each site using a standardized instrument
created for use in this study. Each episode was assigned
a primary cause for the ALT/AST increase based on
review of the electronic medical record. All cases
deemed low certainty or unknown underwent second-
ary review, as were additional specific prespecified di-
agnoses (eg, acute viral hepatitis secondary to
Epstein–Barr virus).
Results
A total of 416 patients experienced 419 episodes of
ALI. Twenty-nine episodes were excluded, leaving 387
patients and 389 episodes in the final analysis (Table 1).
The 4 most common categories were ischemic hepatitis
(42.7%), pancreatobiliary causes (12.3%), DILI (11.3%),
and acute viral hepatitis (11.3%).
When more extreme increases were examined, the
list of causes narrowed. For patients with an ALT level
5000, acetaminophen DILI and ischemic hepatitis
represented the majority of causes (55.6% and 33.3%,
respectively). For patients with an AST level 5000,
ischemic hepatitis and acetaminophen DILI again
represented the majority of causes, although with the
opposite relative frequency (60.3% and 25.9%,
Abbreviations used in this paper: ALI, acute liver injury; ALT, alanine
aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced
liver injury; VA, Veterans Affairs.
Most current article
© 2019 by the AGA Institute
1542-3565/$36.00
https://doi.org/10.1016/j.cgh.2018.08.016
1202 Breu et al Clinical Gastroenterology and Hepatology Vol. 17, No. 6

Table 1. Causes of Acute Liver Injury

All episodes VA site Transplant site Community site

(n ¼ 389) (n ¼ 145) (n ¼ 165) (n ¼ 79)

Cause N % N % N % N % P valuea

Ischemic hepatitis 166 42.7 74 51.0 65 39.4 27 34.2 .03

Pancreatobiliary causes 48 12.3 11 7.6 21 12.7 16 20.3 .02
DILI 44 11.3 9 6.2 27 16.4 8 10.1 .02
Acetaminophen 26 6.7 3 2.1 19 11.5 4 5.1
Other 18 4.6 6 4.1 8 4.8 4 5.1
Acute viral hepatitis 44 11.3 25 17.2 11 6.7 8 10.1 .01
Acute viral hepatitis C 31 8.0 24 16.6 4 2.4 3 3.8
Acute viral hepatitis B 8 2.1 0 0.0 4 2.4 4 5.1
Acute viral hepatitis Epstein–Barr virus 2 0.5 0 0.0 1 0.6 1 1.3
Acute viral hepatitis A 1 0.3 0 0.0 1 0.6 0 0.0
Acute viral hepatitis cytomegalovirus 1 0.3 1 0.7 0 0.0 0 0.0
Acute viral hepatitis D 1 0.3 0 0.0 1 0.6 0 0.0
Procedural 21 5.7 8 5.5 13 7.9 0 0.0 .04
After partial hepatectomy 11 2.8 6 4.1 5 3.0 0 0.0
After liver transplant 6 1.5 0 0.0 6 3.6 0 0.0
Bland arterial embolization 2 0.5 2 1.4 0 0.0 0 0.0
Transarterial chemoembolization 2 0.5 0 0.0 2 1.2 0 0.0
Other 49 12.6 14 9.7 24 14.5 11 13.9 .40
Muscle disorders 13 3.3 6 4.1 4 2.4 3 3.8
Malignant infiltration 12 3.1 6 4.1 6 3.6 0 0.0
Autoimmune hepatitis 7 1.8 0 0.0 4 2.4 3 3.8
Trauma 3 0.8 0 0.0 3 1.8 0 0.0
Miscellaneousb 14 3.4 2 1.4 7 4.2 5 6.3
Unknown 17 4.4 4 2.8 4 2.4 9 11.4 <.01

a
P values are for comparisons between proportions of causes of transaminase level increases at each study site and were obtained using the chi-squared test or
the Fisher exact test.
b
Miscellaneous causes included those with fewer than 5 total episodes.

respectively). For patients with an initial AST:ALT
ratio greater than 2, 57.0% of causes were ischemic
with no other single diagnosis representing more than
10% of causes.
Discussion
Our large study of 3 centers, encompassing com-
munity, transplant center, and VA practices, captures
the contemporary epidemiology of severe ALI in the
United States. There were 4 main findings. First, we
confirmed that ischemic hepatitis is the leading cause
of severe ALI, particularly when the ALT/AST level is
5000 IU/L. A cannot-miss diagnosis, ischemic hepa-
titis is dangerous not only because it may progress to
liver failure, but because the cause usually is associ-
ated with high mortality.5 As a result, patients
with ischemic hepatitis need urgent medical manage-
ment, often including intensive care. Second, in
contrast to conventional wisdom, we found that
pancreatobiliary pathologies are among the leading
causes of severe ALI. Patients with acute biliary
obstruction may benefit from urgent endoscopic
decompression, necessitating early consideration of
this diagnosis. Third, the epidemiology of acute viral
hepatitis has shifted. Among viral causes, hepatitis C
is more prevalent than typically is recognized,
including 16.6% at the VA site. Fourth, the combination
of ischemic hepatitis, acute viral hepatitis (specifically
acute hepatitis A and B), and acetaminophen DILI
were the cause of ALT/AST levels 1000 IU/L in
just 51.8% of episodes. The fact that nearly half of
episodes have a cause other than the 3 most commonly
cited has important diagnostic and therapeutic
implications.
These results must be interpreted in the context of
the study design. As a retrospective chart review, not all
patients underwent testing for all conditions and our
data relied on accurate and complete evaluation and
documentation.
To improve the care of patients with ALI, the
differential diagnosis must be updated. These data
provide the pretest probabilities for the differential
diagnosis of ALI by hospital type. This study will
enhance clinicians’ ability to accurately assign a dif-
ferential diagnosis to and manage patients presenting
with severe ALI.
References
1. Kasper DL. In: Dennis L, Kasper MD, Channing WE, et al, eds.
Harrison’s principles of internal medicine. 19th ed. New York:
McGraw Hill Education, 2015.
May 2019
2. Galvin Z, McDonough A, Ryan J, et al. Blood alanine amino-
transferase levels >1,000 IU/l - causes and outcomes. Clin Med
(Lond) 2015;15:244–247.
3. Bjornsson HK, Olafsson S, Bergmann OM, et al. A pro-
spective study on the causes of notably raised alanine
aminotransferase (ALT). Scand J Gastroenterol 2016;
51:594–600.
4. Whitehead MW, Hawkes ND, Hainsworth I, et al. A prospective
study of the causes of notably raised aspartate aminotrans-
ferase of liver origin. Gut 1999;45:129–133.
Severe Acute Liver Injury 1203
5. Tapper EB, Sengupta N, Bonder A. The incidence and outcomes
of ischemic hepatitis: a systematic review with meta-analysis.
Am J Med 2015;128:1314–1321.
Reprint requests
Address requests for reprints to: Anthony C. Breu, MD, Veterans Affairs Boston
Healthcare System, 1400 VFW Parkway, West Roxbury, Massachusetts 02132.
e-mail: anthony.breu@va.gov; fax: (857) 203-5549.
Conflicts of interest
The authors disclose no conflicts.