studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 505A
Drug properties (Liver Toxicity Knowledge Base, Drug Discovery
Today 2011) and host factors were compared in DO vs.
NDO. Results: Among the 680 cases, 159 cases (22%) manifested
DILI with 2 to 82 days’ delay after the treatment cessation
(i.e., DO) while 521 (77%) manifested during the drug treatment
(i.e., NDO). 57% of DO cases and 13% of NDO were
Amoxicillin-clavulanate (AMOX/CA) cases. After excluding the
AMOX/CA cases, DO cases had shorter treatment duration
(median: 11 vs. 45 days, p=50% were less prevalent in
DO cases (67% vs. 84%, p=0.003) also drugs with un-metabolized
drug excretion >=50% were more prevalent in DO cases
(25% vs. 9%, p=0.0011). Regarding host manifestations,
eosinophilia was more prevalent in DO cases (30% vs. 19%,
p=0.036), while positive autoantibody was more prevalent in
NDO cases (25% vs. 11%, p=0.024). NDO cases were more
associated with chronic underlying diseases (82% vs. 60%,
p 50% loss, n=14]. Results: The 28 subjects
with bile duct loss included 14 men [5 severe] and 14 women
[9 severe]. The median age was 52.5 [range 11-87] years
those with severe duct loss were younger [47.4 vs 59.7 years,
p=0.04]. Cases were attributed to 20 different agents: 3 to
amoxicillin/clavulanic acid; 3 to temozolomide; 3 to botanicals
[Cactus nopal; Artemisia annua; unknown]; 2 to azithromycin;
and 1 each due to cefalexin, cefazolin, levofloxacin, moxifloxacin,
allopurinol, enalapril, hydralazine, infliximab, lenalidomide,
thalidomide, montelukast, olanzapine, quetiapine,
lansoprazole, omeprazole, metoclopramide and mesalazine.
Median latency to onset was 35 [IQR 19-91] days. The typical
clinical presentation was immuno-allergic, rather than autoimmune-like
disease and was usually cholestatic or mixed, with
median R-value= 2.1 [range 0.1-8.0]. In addition to bile duct
paucity, hepatic pathology showed reactive bile duct injury
and mild portal lympho-histiocytic inflammatory infiltrates.
Eosinophils were noted in 9 biopsies, but peripheral eosinophilia
at disease onset was noted in only 6 patients. 7 of 14
subjects with mild and 8 of 14 with severe injury transitioned
to chronic ongoing injury [laboratory, imaging or clinical evidence
of persisting liver damage > 6 months after onset]. The
likelihood of dying or requiring liver transplantation within 6
months of onset was greater in those with severe bile duct
loss (4/14, 29%) than in mild duct loss (0/14, 0%, p=0.05]
and also greater than in those without duct loss on biopsy
(22/246, 8.9%, p=0.04). Conclusions: Paucity of bile ducts
is an uncommon (6%) histologic feature of acute drug-induced
liver injury, can be caused by diverse agents, both drugs and
botanicals, and often leads to evidence of chronic liver injury,
which, when severe, may lead to premature death or liver
transplantation. Pathogenesis remains imperfectly understood,
but host immune reactions, perhaps influenced by genetic or
environmental factors, appear likely; however, the key antigen[s]
remain unknown.
Disclosures:
Herbert L. Bonkovsky - Advisory Committees or Review Panels: Recordati Rare
Chemicals, Clinuvel, Inc.; Consulting: Alnylam, Inc, Clinuvel, Inc., Clinuvel, Inc.;
Grant/Research Support: Gilead Sciences
Mark W. Russo - Grant/Research Support: Merck, Salix; Speaking and Teaching:
janssen, Gilead, ABBVIE, Salix
The following authors have nothing to disclose: David E. Kleiner, Jiezhun Gu,
Joseph A. Odin, Victor J. Navarro, Maricruz Vega, Jay H. Hoofnagle
598
Caspase Inhibition Switched TNF-α-Induced Apoptosis
to Necroptosis But Not Autophagic Cell Death In
Hepatocytes and Mouse Livers
Hong-Min Ni, Xiaojuan Chao, Mitchell R. McGill, Hartmut
Jaeschke, Wen-Xing Ding; Pharmacology, Toxicology and Therapeutics,
The University of Kansas Medical Center, Kansas City, KS
Hepatocyte death (apoptosis and necrosis) and survival (such
as autophagy) are integrated and play important roles in many
liver diseases such as endotoxin and alcohol-induced liver
injury. How these different cell death and survival pathways
regulate each other remains elusive. We previously demonstrated
that when the cell survival NF-κb pathway was blocked
by a general transcription inhibitor actinomycin D (ActD), tumor
necrosis factor-a (TNF-a) induced apoptosis in primary cultured
mouse hepatocytes, which was completely suppressed by a
general caspase inhibitor, ZVAD. Surprisingly, in the present
study, we found that TNF-a/ActD-treated hepatocytes died
by a necrotic-like cell death evidenced by abundant cellular