title: Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: Association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression.
abstract: OBJECTIVE
  Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC). Patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (encoding the I148M variant) has been associated with advanced fibrosis and HCC. We determined the risk factors for HCC, including the PNPLA3 rs738409 polymorphism, in Japanese patients with biopsy-proven NAFLD.
  
  
  METHODS
  In this retrospective cohort study, we analyzed hepatocarcinogenesis in 238 patients. PNPLA3 rs738409 genotype was determined by allelic discrimination in 130 patients. Among them, 86 patients who were followed up for >5 years and without liver cirrhosis were analyzed to clarify the relationship between PNPLA3 genotype and long-term changes in biomarkers.
  
  
  RESULTS
  Of 238 patients, PNPLA3 genotype frequencies were: CC, 0.14; CG, 0.46; and GG, 0.40. During a follow-up period of 6.1 years, 10 patients (4.2%) with non-alcoholic steatohepatitis developed HCC. The cumulative rate of HCC was 1.9% at the end of the 5th year and 8.3% at the end of the 10th year. Multivariate analysis identified PNPLA3 genotype GG (hazard ratio, 6.36; P = 0.019) and fibrosis stage (fibrosis stage 3/4; hazard ratio, 24.4; P = 0.011) as predictors of HCC development. In the long follow-up cohort, a larger reduction in platelet count was found in the GG group (P = 0.032) despite a larger reduction in alanine aminotransferase (P = 0.023) compared to that in the CC/CG group.
  
  
  CONCLUSIONS
  In Japanese patients with NAFLD, severe fibrosis and PNPLA3 GG genotype were predictors of HCC development, independent of other known risk factors. Patients with the PNPLA3 GG genotype have the potential for a decreased platelet count, even when alanine aminotransferase levels are well controlled.
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Seko
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sumida
authors.affiliation: Center for Digestive and Liver Diseases, Nara City Hospital, Nara.
authors.forename: Saiyu
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Center for Digestive and Liver Diseases, Nara City Hospital, Nara.
authors.forename: Kojiroh
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Taketani
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishiba
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Akira
authors.initials: A
authors.lastname: Okajima
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Umemura
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Taichiro
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Kanji
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Michihisa
authors.initials: M
authors.lastname: Moriguchi
authors.affiliation: Center for Digestive and Liver Diseases, Nara City Hospital, Nara.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kanemasa
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Kohichiroh
authors.initials: K
authors.lastname: Yasui
authors.affiliation: Department of Pathology, Nara City Hospital, Nara, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Imai
authors.affiliation: Department of Pathology, Nara City Hospital, Nara, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Itoh
keywords: NAFLD; PNPLA3; hepatocellular carcinoma