studies

366A AASLD ABSTRACTS HEPATOLOGY, October, 2015
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Carcinogenesis in autoimmune hepatitis type 1 patients
with a long-term follow-up in Japan
Teruko Arinaga-Hino 1 , Tatsuya Ide 1 , Ichiro Miyajima 1 , Kei Ogata 1 ,
Reiichiro Kuwahara 1 , Keisuke Amano 1 , Kazunori Noguchi 2 , Kunihide
Ishii 3 , Kunitaka Fukuizumi 4 , Koji Yonemoto 5 , Takuji Torimura
1 ; 1 Division of Gastroenterology, Department of Medicine,
Kurume Univ.School of Medicine, Kurume, Japan; 2 Omuta City
Hospital, Omuta, Japan; 3 Asakura Medical Association Hospital,
Asakura, Japan; 4 National Kyushu Medical Center, Fukuoka,
Japan; 5 The Biostatistics Center, Kurume University School of Medicine,
Kurume, Japan
Backgrounds/Aims: The risk of carcinogenesis in autoimmune
diseases is high and has been attributed to immunological
abnormalities, the use of immunosuppressive agents, and/or
chronic inflammation. The aim of the present study was to determine
the incidence and risk of carcinogenesis in patients with
autoimmune hepatitis (AIH) type 1 in a large-scale population
with a long-term follow-up in Japan. Methods: Two hundred
and fifty-six patients diagnosed with AIH between Apr. 1978
and Mar. 2014 were enrolled (F/M = 226:30; mean age
at diagnosis AIH, 57.7 yrs). They had no malignancy before
or within 1 yr of being diagnosed with AIH. A person-year
calculation was performed for AIH patients, and the numbers
of expected events were clarified using data from “A Study
of 28 Population-based Cancer Registries for the Monitoring
of Cancer Incidence in Japan (MCIJ) Project (2010)” in order
to determine the standard incident rate (SIR) of each type of
malignancy. Biochemical data regarding carcinogenesis and
its background factors were also examined using a proportional
hazards model, adopting the Kaplan-Meier method. The
present study was approved by the proper Ethics Committee.
Results: The mean observation period was 8.2 yrs (The person
years at risk were 2,107; Females; 1,878, Males; 229).
Twenty-seven patients developed malignancy (F:M = 24:3).
The mean observation period of carcinogenesis from AIH diagnosis
was 10.3 yrs. The number of patients with hepatobiliary
cancer (Ca) was 11 (hepatocellular carcinoma; 10, cholangiocarcinoma;
1), gastric Ca; 3, pancreatic Ca; 2, oral/pharyngeal
Ca; 2, colorectal Ca; 2, breast Ca; 1, lung Ca; 1, acute
myeloid leukemia; 1, malignant lymphoma 1, and malignant
melanoma; 1. The overall SIR for malignancies in AIH was
significantly high at 2.04 (95% CI 1.34-2.96), and was particularly
high among females at 2.49 (95% CI 1.60-3.71). SIR for
hepatobiliary Ca was 14.14 (95% CI 7.05-25.30), and was
markedly high for females at 21.83 (95% CI 10.45-40.16).
SIR for oral/pharyngeal Ca was significantly high for females
at 14.61 (95% CI 1.64-52.77). No significant differences
were observed in SIR among the other types of malignancies
examined. The risk factors for overall carcinogenesis at the
diagnosis of AIH were identified as low levels of alanine aminotransferase
(p=0.0053), a low platelet count (p=0.0087),
and liver cirrhosis (p=0.0067). No significant differences were
observed among the treatment regimens, such as prednisolone,
azathioprine, and ursodeoxycholic acid. Conclusion: The
risk of malignancies was generally high among AIH patients.
The risk of carcinogenesis needs to be carefully considered in
patients with AIH.
Disclosures:
The following authors have nothing to disclose: Teruko Arinaga-Hino, Tatsuya
Ide, Ichiro Miyajima, Kei Ogata, Reiichiro Kuwahara, Keisuke Amano, Kazunori
Noguchi, Kunihide Ishii, Kunitaka Fukuizumi, Koji Yonemoto, Takuji Torimura
305
Immunity in HLA-DR4 expressing healthy and autoimmune
hepatitis induced NOD mice
Muhammed Yuksel 1,2 , Xiaoyan Xiao 1,3 , Kathie Béland 4 , Pascal
Lapierre 4 , Fernando Alvarez 4 , Isabelle Colle 2 , Yun Ma 5 , Li Wen 1 ;
1 Endocrinology, Yale university, New haven, CT; 2 Internal medicine,
Ghent university hospital, Ghent, Belgium; 3 Department of
Nephrology, Shangdong University, Shangdong,., China; 4 Division
of Gastroenterology, Hepatology and Nutrition, Sainte-Justine
University Hospital, Montreal, QC, Canada; 5 Institute of Liver studies,
Kings College London, London, United Kingdom
Autoimmune hepatitis (AIH) is a chronic progressive inflammatory
liver disease, characterized by interface hepatitis, positivity
for autoantibodies and hyper-gammaglobulinemia. There are
two types of AIH, type-1 (AIH-1) being characterized by seropositivity
for anti-smooth muscle and/or anti-nuclear (SMA/
ANA), and type-2 (AIH-2) by positivity for anti-liver kidney microsomal
type 1 (anti-LKM1) and/or anti-liver cytosol type 1
(anti-LC1) autoantibodies. Cytochrome P4502D6 (CYP2D6)
has been defined as the antigenic target of anti-LKM1 and
formiminotransferase cyclodeaminase (FTCD) as the target
for anti-LC1. The development of AIH is linked to the Human
Leukocyte Antigen (HLA) alleles, -DR3 for AIH-1 and -DR7 for
AIH-2. However, the role of HLA-DR4 has been controversial,
being the second disease predisposition gene in adults with
AIH-1 and protective gene in pediatric patients. In this study,
we investigated the role of HLA-DR4 transgene, expressed on
non-obese diabetic (NOD) mice (DR4), healthy (baseline) mice
and also after the AIH induction by immunization with the DNA
coding for human CYP2D6/FTCD fusion protein. Immunization
of wild type (WT) NOD and DR4 mice leads to a sustained
mild elevation of alanine aminotransferase (ALT), development
of anti-LKM1/anti-LC1, and chronic immune cell infiltration,
mild parenchymal fibrosis and some plasma cell infiltration.
Although these parameters were more slightly pronounced in
DR4 mice than in WT control mice, the pathogenic role of
HLA-DR4 remains uncertain. However, livers from DR4 mice
contained less regulatory T cell (Tregs) which had decreased
PD-1 expression and a dysfunction to suppress alloreaction.
We also showed that, T cells and antigen presenting cells,
such as macrophages and dendritic cells, were already activated
in non-immunized naïve (healthy) DR4 mice compared to
naïve WT NOD. These results show that HLA-DR4 molecule is
involved in the spontaneous activation of the immune system,
facilitating the induction of AIH.
Disclosures:
Isabelle Colle - Advisory Committees or Review Panels: Janssen; Grant/Research
Support: Bayer; Patent Held/Filed: Trombogenics; Speaking and Teaching: BMS
The following authors have nothing to disclose: Muhammed Yuksel, Xiaoyan
Xiao, Kathie Béland, Pascal Lapierre, Fernando Alvarez, Yun Ma, Li Wen
306
Autoimmune Hepatitis Disproportionately Affects People
of Color
Michele M. Tana 1,2 , Edward W. Holt 3 , Robert J. Wong 4 , Justin L.
Sewell 1 , Mandana Khalili 1 , Jacquelyn J. Maher 1,2 ; 1 Department of
Medicine, Division of Gastroenterology, University of California,
San Francisco, San Francisco, CA; 2 UCSF Liver Center, University
of California, San Francisco, San Francisco, CA; 3 Department of
Transplantation, Division of Hepatology, California Pacific Medical
Center, San Francisco, CA; 4 Department of Gastroenterology
and Hepatology, Alameda Health System, Oakland, CA
Autoimmune hepatitis (AIH) is an uncommon disease that
affects patients of all ethnicities, and there have been reports
that its natural history varies in patients of different ethnic back-