studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 507A
genes and located in the following genes ABCB4, ABCC2,
ATP8B1, HSD3B7, NOTCH2 (1 SNV each) and SERPINA1,
TJP2 (2 SNVs each). The 5 SNVs from the PSC GWAS list were
located in the genes CD226, GPR35, MST1 (1 SNV each) and
SH2B3 (2 SNVs). Overall, 9/10 childhood-onset PSC patients
had at least one of the SNVs (4 patients with 1 SNV, 4 with
2 SNVs and 1 patient with 3 SNVs). Conclusions: Patients
with childhood-onset PSC harbor rare, deleterious variants in
genes involved with cholestasis and risk of PSC, suggesting that
disease in these patients may lie along a spectrum between
syndromic forms of cholestatic disease and classical PSC. Additional
studies including patients with more-typical disease onset
will help to confirm this finding and may establish a role for
these genes in adult disease.
Disclosures:
The following authors have nothing to disclose: Brian D. Juran, Aliya Gulamhusein,
Saurabh Baheti, Konstantinos Lazaridis
well that patients should be treated early in disease, when
ALP and bilirubin levels first exceed ULN, and that patients be
treated to the lowest levels possible to avoid liver transplant
and premature death.
Disclosures:
David Jones - Consulting: Intercept, Pfizer, Novartis; Speaking and Teaching:
Falk, Shire
Henk R. van Buuren - Grant/Research Support: Intercept, Zambon Nederland BV
The following authors have nothing to disclose: Bettina E. Hansen, Willem J.
Lammers, George F. Mells, Marco Carbone
601
Convergence of Two Predictive Models of Risk Reduction
in Patients with Primary Biliary Cirrhosis (PBC)
Bettina E. Hansen 1 , Willem J. Lammers 1 , David Jones 2 , Henk R. van
Buuren 1 , George F. Mells 3 , Marco Carbone 4 ; 1 Erasmus MC, University
Medical Center Rotterdam, Rotterdam, Netherlands; 2 Institute
of Cellular Medicine, Newcastle University Medical School,
Newcastle Upon Tyne, United Kingdom; 3 Academic Department
of Medical Genetics, University of Cambridge, Cambridge, United
Kingdom; 4 Division of Gastroenterology and Hepatology, Department
of Medicine, Addenbrooke’s Hospital, Cambridge, United
Kingdom
Background: Two recent analyses on prognostic algorithms
in large PBC cohorts provides a unique opportunity to test the
replicability of effect. Objective: The goal of this study was to
apply common assumptions to algorithms developed by the
Global PBC and UK PBC cohorts to predict liver transplant-free
survival, and to determine if the models are comparable in
terms of quantified risk. Methods: The Global PBC cohort
consists of 4,565 PBC patients treated with ursodeoxycholic
acid (UDCA), recruited from 15 centers in 8 countries. An
algorithm predicting liver transplant and all-cause mortality
was created using Cox proportional hazards regression on
a derivation sample (n=2488), and validated in a matched
sample (n=1631). Predictor variables included: age, and
serum bilirubin, alkaline phosphatase, albumin and platelet
count measured 1 year after UDCA initiation. The UK PBC
cohort (n=4022) was recruited from 150 National Health Service
(NHS) Trusts across the UK and includes both patients
treated and not treated with UDCA. An algorithm predicting
liver transplant and liver-related death was derived from 2414
patients and validated in 1608 patients. The predictor algorithm
includes serum bilirubin, alkaline phosphatase, albumin,
platelet count and ALT. The absolute risk for liver transplant and
survival was calculated using equivalent fixed inputs for albumin
(40 g/L or 1.143 of LLN=35) and platelets (120 X 10 9 /L);
age set at 65 and ALT at 84 U/L. Bilirubin varied as a function
of ULN: 1X = 17 mmol/L; 2X = 34 mmol/L; 3X = 51 mmol/L;
4X = 68 mmol/L and ALP by 10 U/L, with range as a function
of ULN: 1X = 150 U/L to 4X = 600 U/L. Results are shown in
the figure below. Conclusion: The calculations showed comparability
at bilirubin > 2ULN and near comparability at bilirubin
at ULN, providing further compelling evidence that both ALP
and bilirubin are reliable predictors of PBC outcomes. The convergence
of data from these models argues strongly for a reassessment
of treatment goals. These results indicate that patients
with advanced disease are at highest need of treatment, as
602
Differentially Expressed Plasma miRNAs as Novel Biomarkers
for the Early Detection of Primary Sclerosing
Cholangitis and Cholangiocarcinoma
Francesca Bernuzzi 2 , Francesco Marabita 4 , Ana Lleo 2 , Ilaria Bianchi
2 , Massimiliano Mirolo 5 , Marco Marzioni 6 , Gianfranco Alpini 7 ,
Domenico Alvaro 8 , Kirsten M. Boberg 9 , Massimo Locati 5 , Guido
Torzilli 10 , Lorenza Rimassa 11 , Fabio Piscaglia 12 , Xiao-Song He 1 ,
Patrick S. Leung 1 , Christopher L. Bowlus 3 , Guo-Xiang Yang 1 , M.
Eric Gershwin 1 , Pietro Invernizzi 2 ; 1 Internal Medicine, University
of California, Davis, CA; 2 Liver Unit and Center for Autoimmune
Liver Diseases, Humanitas Clinical and Research Center, Milan,
Italy; 3 Division of Gastroenterology and Hepatology, University of
California at Davis, Davis, CA; 4 Unit of Computational Medicine,
Department of Medicine, Karolinska Institute, Stockholm, Sweden;
5 Department of Medical Biotechnologies and Translational Medicine,
University of Milan, Milan, Italy; 6 Department of Gastroenterology,
Universita Politecnica delle Marche, Ancona, Italy;
7 Department of Medicine, Division of Gastroenterology, Texas
A&M University Health Science Center, Temple, TX; 8 Department
of Clinical Medicine, Division of Gastroenterology, University of
Rome, Rome, Italy; 9 Medical Department, Rikshospitalet, Oslo,
Norway; 10 Liver Surgery Unit, Department of Surgery, Humanitas
Clinical and Research Center, Milan, Italy; 11 Medical Oncology
and Hematology Unit, Humanitas Clinical and Research Center,
Milan, Italy; 12 Department of Medical and Surgical Sciences
DIMEC, Alma Mater Studiorum, University of Bologna, Bologna,
Italy
Background: Cholangiocarcinoma (CCA) is the second most
common primary hepatic malignancy and a frequently fatal
complication of primary sclerosing cholangitis (PSC) with the
highest incidence within the first 2.5 years following the diagnosis
of PSC. The lack of sensitive and specific biomarkers
poses a major challenge in the early diagnosis of CCA in the
setting of PSC. Specific plasma microRNAs (miRNAs) have
been reported in a number of inflammatory and neoplastic
conditions. The aim of the study was an intensive discovery
phase to identify specific plasma miRNAs as diagnostic biomarkers
for PSC and CCA. Methods: Ninety human plasma
samples (30 PSC, 30 CCA, and 30 healthy subjects) were
surveyed for the levels of 667 miRNAs by qRT-PCR to identify
disease-associated candidate miRNAs (discovery phase).
miRNAs that demonstrated an absolute log 2
(fold change) >
1, mean Ct < 30, and p < 0.05 were selected for validation.
Candidates were validated in an independent cohort of
130 samples (40 PSC, 40 CCA, 10 primary biliary cirrhosis