studies

1048A AASLD ABSTRACTS HEPATOLOGY, October, 2015
1722
Liver Disease in Subjects with N-Glycanse-1 Deficiency
Shilpa Lingala 1 , David E. Kleiner 6 , Christina Lam 2 , Lynne A.
Wolfe 3,5 , Carlos R. Ferreira 2 , Donna Krasnewich 4 , William A.
Gahl 2,5 , Marc G. Ghany 1 ; 1 Liver Diseases Branch, National Institute
of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health, Bethesda, MD, Betheda, MD; 2 Medical Genetics
Branch, National Human Genome Research Institute, NIH,
Bethesda, MD; 3 Undiagnosed Diseases Program, NIH, Bethesda,
MD; 4 Division of Genetics and Developmental Biology,, National
Institute of General Medical Sciences, NIH, Bethesda, MD; 5 Office
of the Clinical Director, National Human Genome Research Institute,
NIH, Bethesda, MD; 6 Laboratory of Pathology, National Cancer
Institute, Bethesda, MD
Background: N-glycanase 1 (NGLY1) deficiency is a newly
described inherited disorder of glycoprotein degradation.
N-glycanase is a cytosolic enzyme that cleaves intact glycans
off of misfolded N-linked glycoproteins after they have been
processed by the endoplasmic reticulum associated degradation
pathway. Deficiency of NGLY1 in humans manifests as
developmental delay, multifocal epilepsy, involuntary movements,
low tear production and elevation of liver-associated
enzymes. Aim: To describe the spectrum of liver disease in
subjects with NGLY1 deficiency. Methods: 11of 27 subjects
with confirmed NGLY1 deficiency worldwide were evaluated
at the Clinical Center, NIH between June 2014-May 2015.
Some have been previously reported. A careful history and
physical exam were performed and all available retrospective
clinical data including liver biopsy were reviewed. At the Clinical
Center, subjects underwent a comprehensive evaluation
for liver disease including liver-associated enzymes, serologic
testing for known causes of chronic liver disease, abdominal
ultrasound and transient elastography to assess liver stiffness.
Liver biopsies, if available, were evaluated by an expert hepatopathologist.
Results: There were 6 females and 5 males with
a mean age 9.9 years (2.4-21 yrs.). All were Caucasian.
6/11(55%) had a history of neonatal jaundice, 50% of whom
required phototherapy. 8 subjects had ALT levels tested within
the first 2 years of age, mean ALT 141 U/L (12-1000 U/L). ALT
levels were elevated in 7/8 (87%) and remained persistently
elevated in only 2 (51 & 137 U/L) over a mean follow-up of
2.5 years. Alkaline phosphatase was elevated for age in 7 subjects.
Other causes of chronic liver disease were excluded in all
11 subjects. Liver tissue was available on 3/11 and revealed
cirrhosis in 2 and bridging fibrosis in one subject. Mild to
moderate steatosis was seen in all biopsies. Scattered PAS
positive macrophages were seen in biopsies from 2 subjects
but no inclusion bodies were noted. Transient elastography
stiffness scores were elevated (17.1, 9.5 and 8.1 Kpa) in the
3 subjects with advanced fibrosis but normal in the remainder.
One subject with cirrhosis developed possible HCC at age 1.2
years and underwent liver transplantation. There was no noted
association of liver disease progression with specific genotype.
Conclusion: Chronic liver disease was common among subjects
with NGLY1 deficiency, particularly during infancy, but
liver-associated enzymes improved over time reminiscent of
alpha-1 antitrypsin deficiency. Progression of liver disease to
cirrhosis was observed and HCC may occur. The pathogenesis
of the liver disease is currently being evaluated.
Disclosures:
The following authors have nothing to disclose: Shilpa Lingala, David E. Kleiner,
Christina Lam, Lynne A. Wolfe, Carlos R. Ferreira, Donna Krasnewich, William
A. Gahl, Marc G. Ghany
1723
Primary immunodeficiencies in cryptogenic acute liver
failure in children: a single centre experience
Rajeev Khanna 1 , Susan Height 3 , Kimberly Gilmour 2 , Nedim
Hadzic 1 ; 1 Paediatric Liver unit, King’s College Hospital, London,
United Kingdom; 2 Immunology, Great Ormond Street Hospital,
London, United Kingdom; 3 Paediatric Haemato-Oncology Unit,
King’s College Hospital, London, United Kingdom
Background: Majority of paediatric acute liver failure (PALF)
cases remain cryptogenic. Haemophagocytic lymphohistiocytosis
(HLH) is an under-diagnosed clinical syndrome which is
often associated with primary immunodeficiency disorders.
HLH is occasionally observed in ALF. Aim: We aimed to identify
primary immunodeficiency states associated with HLH,
observed in PALF between January’99 and May’15. Methods:
We retrospectively analysed our database for children with
HLH and investigated their demographic, clinical, biochemical
and immunological markers, management and outcome.
We used standard international criteria for definition of PALF.
Children with histological evidence of haemophagocytosis, or
with deficient proteins involved in lymphocyte granule-mediated
cytotoxic pathway including perforin, signaling lymphocyte-activating
molecule-associated protein (SAP), granule
release assay (CD107a), Munc-13-4, syntaxin 11, syntaxin
binding protein-2 on flow cytometry were enrolled. Mutational
analysis was performed for PRF1, UNC13D, STX11, STXBP2,
RAB27A, XLP-1/SH2D1A, XIAP/BIRC4, CD27 and MAGT1
genes. Their outcome was compared with historical controls
with PALF from our centre. Results: We identified 16 children
with HLH – 8 had histological evidence, whereas 10 had deficient
proteins (6 perforin, 3 SAP and 1 Munc-13-4). Males
(81%) predominated. Four (25%) belonged to consanguineous
families. Ten (62%) were younger than 6 months. Jaundice,
fever and encephalopathy were present in 12, 12 and 8 cases,
while hepatomegaly, splenomegaly and lymphadenopathy
were there in 15, 13 and 4 children, respectively. Median
peak bilirubin, AST and INR were 158 micromol/L, 1870 IU/L
and 3.47. Hyperferritinemia, hypertriglyceridemia and hypofibrinogenemia
were present in 14, 8 and 5 children. Mutations
were identified in PRF1, SAP/XLP-1 and RAB27A genes in
7, 3 and 1 patients, respectively. All patients were managed
as per standard intensive care therapy. Their clinical course
was complicated by marrow failure, ventilatory requirement,
systemic inflammatory response syndrome and multi-organ dysfunction
syndrome in 13, 9, 6 and 5 patients, respectively. 2
children underwent liver transplantation – one of them died few
months later due to neurological events. One underwent bone
marrow transplantation. 1-year mortality was 31% which was
higher than historical cohort. Conclusion: Identification of this
group of children with ALF is important for their prognostication
and family screening. In PALF, diagnosis of HLH needs to
be pursued by combination of biochemical, histological and
immunological markers, particularly in young male children
from consanguineous families.
Disclosures:
Nedim Hadzic - Consulting: Alnylam; Speaking and Teaching: Synageva
The following authors have nothing to disclose: Rajeev Khanna, Susan Height,
Kimberly Gilmour