studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1149A
aims were to (1) assess the diagnostic yield of the EWG clinical
chemistry criteria for DILI when applied to individual case
safety reports of VEM, (2) describe the limitations of the EWG
criteria in real-world application and (3) present the modifications
implemented. Methods: We conducted a retrospective
review and analysis of the EWG algorithm and diagnostic criteria
for identifying and evaluating DILI cases for VEM. Results:
228 serious, medically confirmed cases with hepatic adverse
events were included; 81 met the DILI EWG criteria threshold:
a diagnostic yield of 35.5%. The EWG algorithm was modified
at 3 levels: (1) The CTCAE severity grading was substituted
for actual laboratory values. (2) Cases that did not meet the
DILI criteria but were reported as hepatic failure or had fatal
outcomes were included during causality assessment so clinically
significant cases were not missed. (3) To allow flexibility
with missing data, the WHO global introspection method for
causality assessment was used instead of the CIOMS Roussel
Uclaf Causality Assessment Method (RUCAM). Conclusions:
The DILI EWG clinical chemistry criteria and algorithm provide
an objective and systematic approach to the assessment of DILI
within the postmarketing setting. The modifications proposed
herein address the inadequate case information from spontaneous
sources.
Disclosures:
Marie Lou Gacusan Munson - Employment: Genentech
Liat Schwartz Sagi - Employment: Genentech-Roche
The following authors have nothing to disclose: Mason Shih, Edwin Tucker
1930
Minocycline hepatotoxicity: Clinical characterization and
identification of HLA- B*35:02 as a risk factor
Thomas J. Urban 1,2 , Paola Nicoletti 3 , Naga P. Chalasani 4 , Jose
Serrano 5 , Andrew Stolz 6 , Ann K. Daly 7 , Guruprasad P. Aithal 8 ,
John F. Dillon 9 , Huiman X. Barnhart 10 , Paul B. Watkins 2 , Robert
J. Fontana 11 ; 1 Eshelman School of Pharmacy, University of North
Carolina at Chapel Hill, Chapel Hill, NC; 2 Hamner Institute for
Drug Safety Sciences, Durham, NC; 3 Center for Computational
Biology and Bioinformatics, Columbia University, New York,
NY; 4 Indiana University School of Medicine, Indianapolis, IN;
5 National Institute of Diabetes Digestive and Kidney Diseases,
Bethesda, MD; 6 University of Southern California, Los Angeles,
CA; 7 University of Newcastle, Newcastle, United Kingdom; 8 Nottingham
University, Nottingham, United Kingdom; 9 University of
Dundee, Dundee, United Kingdom; 10 Duke University, Durham,
NC; 11 University of Michigan, Ann Arbor, MI
Prolonged minocycline use has been associated with rare
instances of hepatotoxicity that can present with prominent
autoimmune features in previously healthy individuals. Prior
genome-wide association studies (GWAS) have demonstrated
human leukocyte antigen (HLA) polymorphisms that are associated
with DILI susceptibility to various agents. The aim of this
study was to identify potential genetic determinants of minocycline
DILI in a well-phenotyped cohort of patients. METHODS: A
total of 25 Caucasian patients (22 from DILIN, 3 from iDILIC)
with DILI due to minocycline underwent genome-wide genotyping
and were compared to population controls. Coding
sequences of HLA alleles were imputed based on SNP genotypes
in the HLA region. Verification of HLA carrier status was
undertaken using sequence-based HLA typing and included an
additional 2 DILIN cases that were not included in the GWAS.
RESULTS: Amongst the 26 cases from DILIN with complete clinical
information, 73.1% were female with a median age of
19.5 years (range: 15 to 61). The median latency from drug
start to DILI onset was 330 days (range: 15 to 1350) with 70%
of cases presenting after 6 months of minocycline exposure. At
DILI onset, 50% were jaundiced, 19% reported rash, and 31%
had fever but only 4% had eosinophilia. At presentation, 82%
had acute hepatocellular liver injury, median ALT of 1212 IU/L
(range: 70 to 2500), median bilirubin of 4.5 mg/dl (range:
0.2 to 16.7), 92% had a + ANA and 29% had a + SmAb.
During follow-up, 46% were treated with corticosteroids and
the median time to ALT normalization was 93 days. None of
the subjects died or required a liver transplant but 25% had evidence
of chronic liver injury at 6 months of follow-up. GWAS
revealed a strong association between HLA-B*35:02 and risk
for minocycline-DILI, with a carrier frequency of 16% in DILI
cases compared to 0.6% in population controls (Odds Ratio:
29.6, 95% CI: 9.0-97.5, p=2.5 x 10 -8 ). Verification of HLA-
B*35:02 imputation was confirmed by sequence-based HLA
typing. HLA-B*35:02 carriers had a lower R-value at presentation
(9 vs. 26, p=0.018) but otherwise had similar presenting
features and outcomes compared to non-carriers. HLA-B*35:02
has been shown to hasten progression to AIDS among HIV
patients, but has not previously been associated with any drugor
liver-related phenotypes. CONCLUSIONS: Long-term treatment
with minocycline can result in infrequent severe acute
hepatocellular liver injury with prominent autoimmune features
in young female patients. HLA-B*35:02 is a rare HLA allele
that is strongly associated with minocycline-DILI, and may be a
useful diagnostic marker of this serious adverse event.
Disclosures:
Naga P. Chalasani - Consulting: Abbvie, Lilly, Celgene, Tobira, NuSirt, Takeda,
Merck/Anthem, Salix; Grant/Research Support: Intercept, Gilead, Galectin
Paul B. Watkins - Consulting: Abbott, Actelion, Boerringer-Ingelheim, Cempra,
Alecra, Roche, Merck, Reservlogix, Intercept, Janssen, Novartis, Otsuka, Pfizer,
Sanolfi, Takeda, UCB, Bristol-Myers Squibb, GSK
Robert J. Fontana - Consulting: GlaxoSmithKline, CLDF; Grant/Research Support:
Gilead, vertex, BMS, Jansen, Gilead
The following authors have nothing to disclose: Thomas J. Urban, Paola Nicoletti,
Jose Serrano, Andrew Stolz, Ann K. Daly, Guruprasad P. Aithal, John F. Dillon,
Huiman X. Barnhart
1931
Liver Disorders that can Masquerade as Drug-Induced
Liver Injury
Don C. Rockey 1 , Paul H. Hayashi 2 , Hans L. Tillmann 3 , Jiezhun
Gu 3 , Marwan Ghabril 4 , Jawad Ahmad 5 , Andrew Stolz 7 , Robert J.
Fontana 8 , Jay H. Hoofnagle 6 ; 1 Medical University of South Carolina,
Charleston, SC; 2 University of North Carolina, Chapel Hill,
NC; 3 Duke University, Durham, NC; 4 Indiana University, Indianapolis,
IN; 5 Mount Sinai, New York, NY; 6 NIH, Bethesda, MD;
7 University of Southern California, Los Angeles, CA; 8 University of
Michigan, Ann Arbor, MI
Background: Drug-induced liver injury (DILI) is a diagnosis of
exclusion, and requires a high degree of clinical suspicion.
The aim of this study was to better understand the features