studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 245A
LTx. However, prognostic models based on population-based
cohorts are lacking. Various biomarkers of disease progression
have been assessed for PSC, and the potential prognostic
value of serum alkaline phosphatase (ALP) over time has been
discussed. The aim of this study was to create a prognostic
model for PSC consisting of disease characteristics and biochemical
variables, and to validate this model in an external
cohort. Methods 692 PSC patients were identified in a large,
population-based PSC cohort from the Netherlands. Disease
characteristics and biochemical variables during long term
follow-up (FU) were retrieved from patient records. Clinical
endpoints were: development of cholangiocarcinoma, LTx,
or PSC-related death. Biochemical tests were transformed by
log transformation, missing values were imputed by multiple
imputation. All variables were assessed as potential predictors
of survival by univariate analysis. To calculate the prognostic
index (PI), a Cox proportional hazards model was developed
and internally validated with bootstrap. The model was
then validated in an external cohort of 259 PSC patients from
UK. Results The median FU was 85 months (range 0-468
months). All disease characteristics and biochemical variables
were considered for the model. After variable selection by
LASSO, multivariate Cox models were fitted, and parameters
estimated from 20 imputation datasets were averaged. The
following formula was created: PI=1.409*PSC type (0/1) 1
+ 0.021*Age_PSC diagnosis - 2.420*log_AlbuminxULN 2 +
2.073*abs(log_TrombocytesxULN-0.5) 2 + 0.469*log_AspartateAminotransferase(AST)xULN
2 + 0.565*log_ALPxULN 2 +
0.528*log_TotalBilirubinxULN 2 1: PSC type: Large duct=1;
Small duct=0 2: xULN= times upper limit of normal A higher
PI indicated a worse prognosis, corresponding to a shorter
endpoint-free survival. The PI yielded a c-statistic of 0.715 in
the development dataset, 0.705 in internal validation (adjusted
for optimism with 1000 times bootstrap), and 0.683 in the
external validation dataset. Conclusion A novel prognostic PSC
model based on PSC type, age at PSC diagnosis, albumin,
thrombocytes, AST, ALP and bilirubin which shows adequate
performance in internal and external validation cohorts, allows
to determine complication-free survival probability for PSC
patients over time.
Disclosures:
Ulrich Beuers - Consulting: Intercept via University of Amsterdam, Novartis via
University of Amsterdam; Grant/Research Support: Falk, Zambon; Speaking and
Teaching: Falk Foundation, Gilead, Roche, Shire
Cyriel Y. Ponsioen - Advisory Committees or Review Panels: Takeda; Consulting:
AbbVIE; Grant/Research Support: AbbVIE, Schering Plough, Dr. Falk Pharma,
Tramedico Netherlands, Takeda
The following authors have nothing to disclose: Elisabeth M. de Vries, Junfeng
Wang, Kate D. Williamson, Mariska M. Leeflang, Kirsten Boonstra, Roger W.
Chapman, Ronald Geskus
75
Clinical Epidemiology of Primary Biliary Cirrhosis based
on a Large US Laboratory Database: Incidence and
Trends in Serum Alkaline Phosphatase
W. Ray Kim 1 , Tracy J. Mayne 2 , Tonya Marmon 3 , David Shapiro 4 ,
Keith D. Lindor 5 ; 1 Division of Gastroenterology and Hepatology,
Stanford University School of Medicine, Stanford, CA; 2 Outcomes
Research, Intercept Pharmaceuticals, New York, NY; 3 Biostatistics,
Intercept Pharmaceuticals, San diego, CA; 4 Office of the Chief
Medical Officer, Intercept Pharmaceuticals, San Diego, CA; 5 College
of Health Solutions, Arizona State University, Tempe, AZ
Backround/Aims: Large scale epidemiological data on primary
biliary cirrhosis (PBC) are scarce. Using a nationwide database
covering approximately 30% of US adults, we estimate
PBC incidence and describe trends in serum alkaline phosphatase
(ALP) activities following the diagnosis. Methods: Electronic
data from a large commercial laboratory were queried
to extract all AMA and ALP results between Jan 2010 and Dec
2013. Following AASLD guidelines, we defined probable PBC
by positive anti-mitochondrial antibodies (AMA) and elevated
serum ALP. AMA positivity was defined by a titer > 1:20 or M2
antibody > 25.0 U, and elevated ALP (> upper limit of normal
(ULN), 120 U/L) by the peak ALP before and up to 30-days
after the first positive AMA. In subjects with PBC, serum ALP
was followed for 24 months after the first positive AMA (baseline)
and the highest ALP was identified per 6-month interval.
Results: Out of over 576,000 persons receiving AMA testing,
16,492 unique individuals (2.9%) tested positive. In 5,380
(33%), serum ALP was elevated at baseline, while another 727
AMA-positive patients developed elevated ALP subsequent to
a positive AMA result. Thus, a total of 6,107 met the criteria
for probable PBC, giving rise to a crude incidence rate of
5.8 per 100,000 over 4 years. In the figure, of the 5,380
patients, 47% had ALP > x2ULN, including 25% with ALP >
3xULN. Following the diagnosis, the proportion of elevated
ULN decreased, presumably as a result of therapy. By 3-6
months, 61% of patients had ALP < 1.5xULN. Subsequent
trends did not show further improvement in ALP – as of 24
months post diagnosis, 69% had elevated ALP, including 35%
with ALP > 1.5xULN. Conclusion: This largest epidemiological
survey for PBC in US to date suggests that annually more than
5000 Americans meet the diagnosis of probable PBC. Two
years after the diagnosis, more than a third continue to have
significantly elevated ALP.
Disclosures:
W. Ray Kim - Advisory Committees or Review Panels: Bristol Myers Squibb,
Gilead Sciences, Abbvie, Merck
Tracy J. Mayne - Employment: Intercept Pharmaceuticals
Tonya Marmon - Employment: Intercept Pharmaceuticals, Inc; Stock Shareholder:
Intercept Pharmaceuticals, Inc
David Shapiro - Employment: Inttercept Pharmaceuticals; Management Position:
Intercept Pharmaceuticals; Stock Shareholder: Intercept Pharmaceuticals
The following authors have nothing to disclose: Keith D. Lindor