studies

1232A AASLD ABSTRACTS HEPATOLOGY, October, 2015
(38%) patients relapsed biochemically (30% of 27 after phlebotomy
and 50% of 18 after HCQ; Log Rank P=0.14). Relapse
rates at 1, 3, and 5 years after phlebotomy or HCQ were
8% vs. 24%, 30% vs. 30%, and 44% vs. 50% respectively.
Relapse rates after these treatments did not differ by initial
age, sex, race, alcohol use, smoking, HFE (hemochromatosis)
genotypes C282Y/C282Y or C282Y/H63D, estrogen use,
serum ferritin, or time to remission. Compared to non-relapsers,
relapsing patients had higher pretreatment plasma porphyrin
concentrations (14±20 vs.6±5 mcg/dL; P=0.046) and a higher
proportion with HCV (94% vs. 71%, P=0.055). All remained
abstinent from alcohol during treatment. But resumption of alcohol
use tended to be more common among relapsers compared
to non-relapsers (67 vs. 43%, P=0.1). Pooled data on relapse
rate from 14 published studies on 1073 PCT patients showed
relapse rates of 13.5% per year with phlebotomy and 17.9%
per year with low dose hydroxychloroquine or chloroquine.
The end-point of low dose HCQ or chloroquine treatment in all
of these previous studies was normalization of urinary porphyrins
with variable cut-off to define normal levels. Conclusions:
PCT relapses may be more frequent with more severe disease
and after achieving remission with low-dose HCQ than with
phlebotomy. Longer follow-up and a larger sample size are
planned with the Porphyrias Consortium study. The optimal
length and end-point of treatment with low dose hydroxychloroquine
need to be better defined.
Disclosures:
Karl E. Anderson - Consulting: Mitsubishi Tanabe Pharma America, Inc.
The following authors have nothing to disclose: Ashwani K. Singal, Eric Gou,
Maira Rizwan, Marisol Albuerne, Csilla Kormos Hallberg
2101
Hepatocellular Carcinoma in Patients with Wilson’s Disease:
Results of a Single Centre Registry of 262 Patients
Harshad Devarbhavi, Mallikarjun Patil; Department of Gastroenterology,
St. John’s Medical College Hospital, Bangalore, India
Introduction: Although hepatocellular carcinoma (HCC) is a
well recognized complication of cirrhosis of various etiologies,
HCC is believed to be extremely rare in Wilson disease.
Around 30 cases have been reported worldwide illustrating
the rarity of this complication. We undertook this study
to determine the frequency and characteristics of HCC in a
cohort of 262 patients over 19 years Patients and methods:
We reviewed the case records of patients with Wilson disease
from the Wilson disease registry maintained from 1996 to
2014. Diagnosis of Wilson disease was based on a score >
4 developed by the International group at Leipzig (J Hepatol
2012;56:671-85). Patients were treated with D-penicillamine
with or without Zinc Sulfate. Patients were regularly followed
up at 3-6 monthly intervals. Patients with HCC were initially
assessed by ultrasonography of abdomen followed by a contrast
enhance CT scan. Results: We identified 3 cases of HCC
among 262 patients with Wilson disease. All 3 had cirrhosis
with portal hypertension at the time of diagnosis as evidenced
by esophageal varices and ascites. The characteristics of these
patients are depicted in Table. All three had multicentric HCC
and presented with resistant complications of portal hypertension
such as variceal bleeding, resistant ascites and one with
hemoperitoneum. Given the advanced nature of HCC at presentation
only supportive treatment could be given. Conclusions:
The incidence of HCC in a large cohort of 262 patients
is 1.1%. Although low, patients with WD are also at risk for
HCC. HCC appears to be aggressive in our cohort of Wilson
disease. Patients with Wilson disease need to undergo regular
screening for early detection of HCC similar to other etiologies.
Those who are insufficiently chelated appear to be more at risk
for HCC.
Characteristics of three patients with HCC
Disclosures:
The following authors have nothing to disclose: Harshad Devarbhavi, Mallikarjun
Patil
2102
Congenital glycosylation defects mimicking Wilsons disease
in patients with unexplained elevated aminotransferases
and low ceruloplasmin
Jos Jansen 1,2 , Joost Drenth 1 , Dirk Lefeber 2 , Monique van Scherpenzeel
2 ; 1 Gastroenterology & Hepatology, Radboud University
Medical Center Nijmegen, Utrecht, Netherlands; 2 Translational
Metabolic Laboraty, glycosylation disorders, Radboud University
Medical Center Nijmegen, Nijmegen, Netherlands
Introduction Congenital disorders of glycosylation (CDGs) are
a heterogenous group of autosomal recessive metabolic disorders
with abnormal glycosylation as a hallmark. GI tract and
liver symptoms are frequent but often secondary. Here we show
that mutations in two uncharacterized genes are the cause
for a primarily Wilson disease-like liver phenotype in twelve
patients with unexplained glycosylation defects. Methods &
Results These twelve patients (gene A: 5 pt., gene B: 8 pt.)
showed an overlapping phenotype with elevated aminotransferases,
high bone-derived alkaline phosphatase, hypercholesterolemia
and elevated LDL-C. Further hepatic analysis showed
low serum ceruloplasmin levels and liver biopsy indicated fibrosis,
cirrhosis, steatosis and mild hepatic copper accumulation
for some patients. Despite similarities, differences between the
two gene defects were noticed. Gene A patients had a milder
phenotype with slightly elevated aminotransferases and hypercholesterolemia.
In contrast, gene B patients developed hepatosplenomegaly,
resembling a glycogen or lysosomal storage
disease, and end stage liver disease was seen for four patients.
Additionally, for gene B, neurological symptoms were seen.
Disease gene identification was done by functional analysis
of exome sequencing. Based on yeast glycosylation models
and BLAST searches two uncharacterized human proteins were
identified. Subsequently analysis of raw exome sequencing
data indicated incomplete coverage of gene A in a family
where previous linkage and standard exome sequencing filtering
was unsuccessful. Additional screening revealed six families
with missense mutations, all segregating via an autosomal
recessive inheritance. We analyzed intact serum transferrin
via mass spectrometry for abnormal glycosylation and found
a specific Golgi homeostasis defect profile. Additionally, we
incubated patient fibroblasts with metabolic labeled sialic acid.
Upon incorporation, the sialic acid gives a fluorescent signal.
We show that fluorescence is reduced by app. 50% in tested
patients. We transiently transfected HeLa cells with V5-tagged
gene constructs and showed via immunofluorescence that
both proteins are located in the ER-to-Golgi region. Together