studies

1278A AASLD ABSTRACTS HEPATOLOGY, October, 2015
2195
Combined effects of the prosteatotic TM6SF2 and
PNPLA3 mutations on NALFD severity: multicentre biopsy-based
study
Marcin Krawczyk 9,1 , Monika Rau 2 , Jörn Schattenberg 3 , Heike Bantel
4 , Anita Pathil 5 , Münevver Demir 6 , Johannes Kluwe 7 , Tobias
Boettler 8 , Frank Lammert 9 , Andreas Geier 2 ; 1 Laboratory of Metabolic
Liver Diseases, Department of General, Transplant and Liver
Surgery, Medical University of Warsaw, Warsaw, Poland; 2 Division
of Hepatology, Department of Medicine II, University Hospital
Wuerzburg, Wuerzburg, Germany; 3 I. Department of Medicine,
University Medical Center Mainz, Johannes Gutenberg University,
Mainz, Germany; 4 Department of Gastroenterology, Hepatology
and Endocrinology, Hannover Medical School, Hannover,
Germany; 5 Department of Internal Medicine IV, Gastroenterology
and Hepatology, University of Heidelberg, Heidelberg, Germany;
6 Clinic for Gastroenterology and Hepatology, University Hospital
of Cologne, Cologne, Germany; 7 I. Department of Medicine, Hamburg
University Medical Center, Hamburg, Germany; 8 Department
of Medicine II, University Hospital Freiburg, Freiburg, Germany;
9 Department of Medicine II, Saarland University Medical Center,
Homburg, Germany
Introduction: The PNPLA3 (adiponutrin) mutation p.I148M
represents the common genetic risk factor for non-alcoholic
fatty liver disease (NAFLD) and progressive liver fibrosis. Lately
a second prosteatotic variant, TM6SF2 p.E167K, has been
detected (Nat Genet 2014). It remains unclear if this mutation,
alike the PNPLA3 p.I148M variant, increases the risk of
liver fibrosis. In the current study we analyzed the combined
effects of these variants on NAFLD severity in a large cohort
of patients recruited at eight German tertiary referral centres.
Patients and methods: After exclusion of acute or chronic liver
diseases other than NAFLD, 514 patients (age 16 – 88 years,
239 men) were included. In 309 patients liver biopsies were
performed, which were examined by pathologists blinded to
genotyping results. PCR-based assays were used to genotype
the PNPLA3 (rs738409) and TM6SF2 (rs58542926) variants.
Results: The genotype frequencies of the PNPLA3 p.I148M
([CC] = 215, [CG] = 223, [GG] = 76) and the TM6SF2
p.E167K ([CC] = 411, [CT] = 94, [TT] = 9) mutations did not
deviate from Hardy-Weinberg equilibrium. One copy of the
prosteatotic PNPLA3 and TM6SF2 alleles was detected in 58%
and 20% of NAFLD patients, respectively. Patients carrying
the PNPLA3 p.I148M or TM6SF2 p.E167K risk alleles had
significantly (both P < 0.01) increased serum ALT and AST
activities. The PNPLA3 risk genotype [GG] (OR = 2.15; 95%
CI 1.21 - 3.87, P = 0.007), but not the TM6SF2 genotype was
more frequent in individuals scheduled for liver biopsy. Among
biopsied individuals, a total of 149 presented with hepatic steatosis
grades S2 or S3, and fibrosis stage > 1 was detected in
77 patients. The TM6SF2 variant increased the risk of developing
steatosis grade S2 - S3 (OR = 1.52, P = 0.04) but did not
affect fibrosis stage. The PNPLA3 genotype was, in turn, associated
with both steatosis grades S2 - S3 (OR = 1.94, P < 0.001)
and increased hepatic fibrosis (OR = 2.24, P < 0.001). In
patients with the PNPLA3 genotype [GG], the presence of variant
TM6SF2 further increased serum aminotransferase activities
(both P < 0.05) and tended to aggravate hepatic steatosis (P
= 0.09). Conclusions: Our results demonstrate that the PNPLA3
and TM6SF2 variants are associated with increased liver injury
as reflected by serum surrogate and histopathological markers.
The TM6SF2 variant seems to modulate predominantly hepatic
fat accumulation, while the PNPLA3 mutation confers risk of
increased steatosis and fibrosis.
Disclosures:
The following authors have nothing to disclose: Marcin Krawczyk, Monika Rau,
Jörn Schattenberg, Heike Bantel, Anita Pathil, Münevver Demir, Johannes Kluwe,
Tobias Boettler, Frank Lammert, Andreas Geier
2196
Weight Loss Results in Significant Improvements in
Quality of Life for Patients with Nonalcoholic Fatty Liver
Disease
Elliot B. Tapper, Michelle Lai; Gastroenterology, Beth Israel Deaconess
Medical Center, Boston, MA
Background: Nonalcoholic Fatty Liver Disease (NAFLD) is
highly prevalent and associated with decreased quality of life
(QOL). Longitudinal QOL data are lacking. Methods: We prospective
enrolled patients with NAFLD from 2009-2014. All
patients received a liver biopsy, transient elastography, lifestyle
assessment, blood tests and QOL tools including the Chronic
Liver Disease Questionnaire (CLDQ), a validated health-related
quality of life measurement. All patients were followed
for 6 months at which time the patients were re-examined and
re-administered the CLDQ. Our primary outcome was overall
QOL and our principle exposure variable was at least a 5%
decrease in weight. Results: 151 patients were followed for 6
months with complete biochemical and QOL data. The cohort
included 91 (60%) men, aged 51.5 + 12.6 years, 46 (30%)
of whom were diabetic. 30 (21%) had advanced fibrosis or
cirrhosis on biopsy and 67 (47%) had nonalcoholic steatohepatitis
(NASH), as defined by a NAFLD activity score (NAS) >
4. Overall, 47 (31%) patients achieved at least a 5% reduction
in weight. Neither advanced fibrosis (20% vs 22%) nor NASH
(44% vs 54%, p = 0.28) were predictive of weight loss. QOL
improved significantly for patients who achieved at least a
5% reduction in weight, especially in nondiabetic patients,
those with NASH, and without significant fibrosis. The cohort’s
baseline total CLDQ value was 5.6 (4.8 – 6.2). Those who
achieved at least a 5% reduction in weight had a 0.45 (95%
CI:0.24 – 0.66, p