studies

1070A AASLD ABSTRACTS HEPATOLOGY, October, 2015
coma grade (74.3% vs 63.5%), percent waitlisted for transplant
(23.3% vs 20.3%), fraction transplanted (14% vs 7.3%,
p=0.2564) or 21 day spontaneous survival (64.1% vs 70.2%),
overall unadjusted survival (65.1% vs 65.2%). Summary/Conclusions:
The fraction of patients with ALF who have had prior
WLS has been increasing in recent years as WLS becomes
more commonplace. When ALF occurs in a patient with prior
WLS, APAP toxicity is the most likely but not the only diagnosis
observed. Bariatric surgery may predispose women to severe
unintentional liver injury at relatively low APAP doses although
outcomes appear similar with and without WLS.
Disclosures:
William M. Lee - Consulting: Eli Lilly, Sanofi; Grant/Research Support: Gilead,
BMS, Vertex, Merck
The following authors have nothing to disclose: Shannan Tujios, Michelle
Gottfried, Valerie L. Durkalski
1767
Dual Role of Epidermal Growth Factor Receptor (EGFR)
in Liver Injury and Regeneration after Acetaminophen
Overdose in Mice
Bharat Bhushan, Michael Manley, Mitchell R. McGill, Hartmut
Jaeschke, Udayan Apte; Pharmacology, Toxicology & Therapeutics,
University of Kansas Medical Center, Kansas City, KS
Acetaminophen (APAP) overdose is the major cause of acute
liver failure in the US with very limited treatment options.
Compensatory liver regeneration following APAP toxicity is a
critical determinant in final recovery and survival. Epidermal
Growth Factor Receptor (EGFR) signaling is known to play an
important role in liver regeneration after partial hepatectomy.
However, role of EGFR signaling in APAP toxicity and accompanying
compensatory regeneration is completely unknown.
We investigated the role of EFGR in APAP-induced liver injury
and subsequent liver regeneration using pharmacological inhibition
of EFGR signaling in mice by treatment with Canertinib,
a water soluble irreversible EGFR inhibitor. EGFR was remarkably
activated as early as 30 minutes after APAP treatment in
a dose-dependent manner and remained activated up to 24 hr
after APAP treatment. Treatment with Canertinib 1 hr post-APAP
caused robust inhibition of EGFR activation resulting in remarkable
attenuation of APAP-induced liver injury. Canertinib treatment
did not alter APAP-protein adduct formation indicating
APAP metabolism was not altered by EGFR inhibitor treatment.
Interestingly, APAP mediated JNK activation (a key mediator
of APAP toxicity) was not altered by EGFR inhibitor treatment.
In order to study role of EGFR in liver regeneration after APAP
overdose, independent of injury, EGFR inhibitor was administered
12 hr after APAP treatment, which resulted in remarkable
impairment of liver regeneration response without any alteration
of injury. Decreased liver regeneration was associated
with decreased induction of cyclin D1 and decreased phosphorylation
of Rb protein. In conclusion, our study revealed,
for the first time, that EGFR receptor plays an important role in
development of APAP injury but also has a direct role in stimulation
of liver regeneration after APAP overdose. These data
support the hypothesis that EGFR signaling plays dual role in
APAP-induced hepatocyte death and proliferation in liver.
Disclosures:
The following authors have nothing to disclose: Bharat Bhushan, Michael Manley,
Mitchell R. McGill, Hartmut Jaeschke, Udayan Apte
1768
Heat Stroke Leading to Acute Liver Failure: Case Series
from the Acute Liver Failure Study Group
Brian C. Davis 1 , Holly Tillman 2 , Robert J. Fontana 3 , K. Rajender
Reddy 4 , Raymond T. Chung 5 , Brendan M. McGuire 6 , R. Todd Stravitz
7 , William M. Lee 1 ; 1 Division of Digestive and Liver Diseases,
UT Southwestern Medical Center, Dallas, TX; 2 Department of Public
Health Sciences, Medical University of South Carolina, Charleston,
SC; 3 Division of Gastroenterology, University of Michigan Health
System, Ann Arbor, MI; 4 Division of Gastroenterology, University
of Pennsylvania Perelman School of Medicine, Philadelphia, PA;
5 Department of Gastroenterology, Massachusetts General Hospital,
Boston, MA; 6 Division of Gastroenterology and Hepatology,
UAB School of Medicine, Birmingham, AL; 7 Division of Gastroenterology,
VCU Medical Center, Richmond, VA
Introduction: In the United States, a small percentage of cases
of acute liver injury (ALI) and failure (ALF) have been associated
with heat stroke, defined as elevated body temperature
≥40°C with central nervous system dysfunction. This may occur
as classical heat stroke (CHS), defined as exposure to high
environmental temperatures, or exertional heat stroke (EHS),
which occurs after strenuous activity. The aim of this study was
to describe cases of ALI or ALF caused by heat stroke in a large
ALF registry. Methods: Amongst 2,675 consecutive ALI and ALF
subjects enrolled between January 1998 and April 1, 2015,
there were 8 subjects with heat stroke, classified as having
CHS or EHS. The clinical, laboratory, and outcome data were
then compared. Results: Five patients had ALF and 3 patients
had ALI. Six patients had EHS, one with CHS, and one was
unclassified. Seven patients developed acute renal failure, 8
had lactic acidosis, and 6 had rhabdomyolysis. Six patients
underwent cooling treatments, 3 received N-acetyl cysteine
(NAC), 3 required mechanical ventilation, 3 required renal
replacement therapy, 1 underwent liver transplantation, and 2
patients died—both within a day of presentation. All but one
case occurred between June and August (May). No long-term
sequelae were observed in survivors. Conclusions: In the US,
heat stroke accounts for