studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1273A
2185
Serum marker of inflammasome activity correlates with
liver injury in nonalcoholic fatty liver disease and is
influenced by genetic polymorphisms.
Leon A. Adams 1,2 , Alexander Wree 3 , Phillip Melton 4 , Gary P.
Jeffrey 1,2 , Helena Ching 2,1 , Bastiaan de Boer 5 , John K. Olynyk 6 ,
Oyekoya T. Ayonrinde 6 , Trevor A. Mori 1 , Lawrence Beilin 1 , Patricia
Price 7 , Craig E. Pennell 9 , Mohammed Eslam 8 , Jacob George 8 ,
Ariel E. Feldstein 3 ; 1 Medicine and Pharmacology, University of
Western Australia, Nedlands, WA, Australia; 2 Hepatology, Sir
Charles Gairdner Hospital, Nedlands, WA, Australia; 3 Pediatrics,
University of California, San Diego, San Diego, CA; 4 Center of
Genetic Origins of Health and Disease, The University of Western
Australia, Nedlands, WA, Australia; 5 Anatomical Pathology,
PathWest, Nedlands, WA, Australia; 6 Gastroenterology, Fiona
Stanley Hospital, Perth, WA, Australia; 7 School of Biomedical Sciences,
Curtin University, Perth, WA, Australia; 8 Medicine, University
of Sydney, Sydney, NSW, Australia; 9 Womens and Childrens
Health, The University of Western Australia, Perth, WA, Australia
Background and Aims: The NLRP3 inflammasome has been
implicated in the pathogenesis of liver injury in nonalcoholic
fatty liver disease (NAFLD). In humans, mutations of Nlrp3
have functional consequences and result in auto-inflammatory
syndromes. We examined whether single nucleotide polymorphisms
(SNP’s) of the NLRP3 and CARD8 genes of the NLRP3
inflammasome influenced serum inflammatory markers and
fatty liver in a general population based cohort. Secondly, we
examined serum caspase-1 as a novel marker of liver injury
and determined the association between inflammasome SNP’s,
serum caspase-1 and liver injury. Methods: Inflammatory markers
(CRP, IP-10, TNFR1, TNFR2, IL18), liver enzymes and
ultrasound diagnosed fatty liver were assessed in a population-based
cohort (n=1046) of 17-year old adolescents. Serum
caspase-1 activity and protein levels were determined in a
second cohort (n=154) and sub-group (n=20) of subjects with
biopsy proven NAFLD by flourometric assay (Abcam, Cambridge,
MA) and western blot respectively. Liver histology was
evaluated according to the NASH CRN scoring system. Eleven
NLRP3 and CARD8 SNPs were genotyped in both cohorts and
assessed for phenotypic associations. Results: In cohort 1, the
rs2043211 SNP in the CARD8 gene was associated with serum
levels of IP10 (p=0.002), IL18 (p=0.009), sTNFR1 (p=0.04),
sTNFR2 (p=0.04), CRP (p=0.056) and a diagnosis of fatty
liver (adj. odds ratio 1.65, 95% CI 1.09-2.48, dominant allelic
model). Serum IP10 and TNFR2 levels but not SNP genotypes
were positively correlated with hepatic aminotransaminase
levels. In cohort 2, serum caspase-1 activity was significantly
increased in the presence of hepatocellular ballooning, inflammation
and fibrosis (p