studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1047A
1720
Liver Involvement in Turner’s Syndrome, Is Associated
with Extra Hepatic Disease Manifestations
Ohad Etzion 1 , Theo Heller 1 , Ma Ai Thanda Han 1 , Ruchi Patel 1 ,
Christopher Koh 1 , David E. Kleiner 1,2 , Omar Mousa 1 , Rohit
Loomba 1 , Vladimir Bakalov 2 , Carolyn Bondy 2 ; 1 Liver Disease
Branch, NIH, Rockville, MD; 2 Heritable Disorders Branch, NICHID-
NIH, Bethesda, MD
Introduction: Turner’s syndrome (TS) is a genetic disorder
caused by complete, partial lack or structural abnormalities
of the X chromosome. Liver abnormalities are commonly
described in patients with TS, however, little is known about
its association with other clinical features of this syndrome.
Aim: To characterize the spectrum of hepatic involvement and
its correlation with non-invasive biomarkers and systemic manifestations
of disease, in a cohort of patient with TS. Methods:
From 2004-2009, patients with TS followed at the NIH Clinical
Center, were evaluated for suspected liver disease. Biochemical
tests, imaging studies and liver biopsy were performed
as clinically indicated, and assessed for its association with
documented extra hepatic disease manifestations. Results: 133
patients (median age 43 years) were evaluated during this
period. Abnormal ALT, AST and ALP values were found in 47%,
40% and 21% of subjects respectively. Sonographic signs of
steatosis were evident in 42% of patients. Echocardiography
detected congenital heart defects in 42%, major venous anomalies
in 13.4%, and aortic or major arterial anomalies in 8.9%
of subjects. Elevated ALT was associated with presence of
major venous anomalies (p=0.01), but not with arterial vascular
anomalies or congenital heart defects. Association between
hepatic steatosis on ultrasound and major venous anomalies
trended towards statistical significance (p=0.053). Twenty-four
patients underwent liver biopsy. Only 1 biopsy was staged as
Ishak 3, with the rest showing Ishak scores of 0 or 1. Steatosis
was diagnosed in 11 (46%) cases, and nodular regenerative
hyperplasia (NRH) in 6 (25%). Portal tracts with missing bile
ducts, arteries or veins were observed in 78%, 69% and 65%
of biopsies respectively. Presence of a major artery anomaly
was associated with higher rate of missing veins in the portal
tracts (p=0.02), but not with bile duct or artery dropout.
Congenital heart defects, major venous anomalies and other
clinical features such as webbed neck and horseshoe kidney
were associated with neither liver enzyme abnormalities, nor
with liver histological findings. Conclusion: Liver enzyme abnormalities
are common in TS and may reflect unique patterns of
liver injury. As previously reported, steatosis is a dominant form
of liver injury in TS. Abnormalities in hepatic microvasculature
are a common finding in TS that are associated with systemic
vascular anomalies. These findings suggest that liver vascular
changes in TS represent an organ specific manifestation of a
systemic disorder of vascular development, which evolves from
the underlying chromosomal abnormality.
Disclosures:
Rohit Loomba - Advisory Committees or Review Panels: Galmed Inc, Tobira Inc,
Arrowhead Research Inc; Consulting: Gilead Inc, Corgenix Inc, Janssen and
Janssen Inc, Zafgen Inc, Celgene Inc, Alnylam Inc, Inanta Inc, Deutrx Inc; Grant/
Research Support: Daiichi Sankyo Inc, AGA, Merck Inc, Promedior Inc, Kinemed
Inc, Immuron Inc, Adheron Inc
The following authors have nothing to disclose: Ohad Etzion, Theo Heller, Ma
Ai Thanda Han, Ruchi Patel, Christopher Koh, David E. Kleiner, Omar Mousa,
Vladimir Bakalov, Carolyn Bondy
1721
NOTCH2 variants in cholestatic liver disease
Tassos Grammatikopoulos 1 , S. Strautnieks 2 , Melissa Sambrotta 1 ,
Pierre Foskett 2 , Maesha Deheragoda 2 , A. S. Knisely 2 , Richard J.
Thompson 1 ; 1 Institute of Liver Studies, Division of Transplantation
Immunology and Mucosal Biology, King’s College London, London,
United Kingdom; 2 Institute of Liver Studies, King’s College
London, London, United Kingdom
Background: Alagille syndrome (AGS) is an autosomal dominant
multisystem disorder associated with mutations in JAG1
and NOTCH2 in respectively 94% and ~1% of affected
patients. Aim: We report eight cholestatic patients with novel,
or rare NOTCH2 variants. Methods: After biliary atresia and
α-1-antitrypsin deficiency were ruled out, cholestatic patients
in whom clinical features and/or liver histology findings could
not exclude AGS were assessed. NOTCH2 screening was
performed as part of diagnostic next generation sequencing.
Results: Among 302 patients sequenced using a custom-designed
cholestasis gene panel, heterozygous variants in
NOTCH2 were identified in 8 (5 male) patients. Seven variants
were missense changes. One was protein-truncating (Table).
Median age at presentation was 5 weeks (range, 2wks-30yrs)
with jaundice (7), hepatosplenomegaly (1), failure to thrive (4),
pale stools (5), raised transaminases (7) and pruritus (2). Vertebral
and ophthalmological and cardiac abnormalities were not
found in screened patients. Facial characteristics typical of AGS
were identified in patient 1 and in his maternal grandmother
who had the same genetic variant. Liver microscopy showed
lobular cholestasis (5), bile duct paucity (2), and fibrosis (3);
cytokeratin 7, expressed in attenuated biliary radicles, was
aberrantly expressed in hepatocytes (2). Abdominal sonography
and magnetic resonance cholangiography showed bile
duct irregularities (2), abnormal gallbladder (1) and renal cysts
(1). Median serum bilirubin was 105 μmol/L [5-227], AST
86 IU/L [31-319], ALT 90 IU/L [33-195], GGT 172 IU/L [27-
389], albumin 38 g/L [35-30], creatinine 43 μmol/L [13-89],
INR 0.98 [0.94-1.1] and cholesterol 3.89 mmol/L [1.9-5.1].
Patients 2 and 6 underwent liver transplantation before their
1 st birthdays. Family histories included jaundice and gallstones
in maternal grandparents in patient 3, heart murmur in mother
of patient 2 and similar findings on liver biopsy in father of
patient 6. Conclusion: We report the identification of eight
probands with cholestasis and variants in NOTCH2. We could
find clinical features associated with AGS in only a minority of
these patients. None met diagnostic criteria for AGS.
Disclosures:
Richard J. Thompson - Grant/Research Support: Shire; Speaking and Teaching:
Shire
The following authors have nothing to disclose: Tassos Grammatikopoulos,
S. Strautnieks, Melissa Sambrotta, Pierre Foskett, Maesha Deheragoda, A. S.
Knisely