Risk factors for histological progression of nonalcoholic steatohepatitis analyzed from repeated biopsy cases.

BACKGROUND AND AIM The most important prognostic factor for non-alcoholic steatohepatitis (NASH) is liver fibrosis. The aim of this study is to examine clinical parameters involved in pathological progression in NASH patients who underwent repeated liver biopsy and to analyze the response to treatment with respect to NASH-related single nucleotide polymorphisms (SNPs). We performed longitudinal analysis of genetic and clinical factors associated with progression of NASH. METHODS Eighty NASH patients who had undergone serial liver biopsies were enrolled in this retrospective cohort study. Histological exacerbation was determined based on NAFLD activity score (NAS) and liver fibrosis. RESULTS 22.5% had progression of fibrosis, 22.5% had improvement of fibrosis, and 55.0% had no change. NAS increased in 12.5%, decreased in 61.3%, and remained stable in the remaining 26.3%. We examined factors associated with histological progression versus non-progression. Poor response of ALT levels, increase in HbA1c levels, and presence of the TNF risk allele in the rs1799964 SNP were identified as independent risk factors contributing to histological progression in NASH patients. In addition, we found that the histological progression rate varies with ALT response, HbA1c levels, and rs1799964 genotype. CONCLUSIONS In this study, we clarified the serum ALT level and the clinical significance of HbA1c to evaluate the progression of fibrosis in Japanese NASH patients. Furthermore, the TNF SNP was more likely to be involved in the response than PNPLA3 SNP. By simultaneously evaluating three factors, it is possible to estimate the risk of histological progression more accurately.

[1]  B. Wang,et al.  Correlation Between Adiponectin Gene rs1501299 Polymorphism and Nonalcoholic Fatty Liver Disease Susceptibility: A Systematic Review and Meta-Analysis , 2019, Medical science monitor : international medical journal of experimental and clinical research.

[2]  P. Banerjee,et al.  Genetic and Epigenetic Culprits in the Pathogenesis of Nonalcoholic Fatty Liver Disease. , 2018, Journal of clinical and experimental hepatology.

[3]  P. Gallo,et al.  Promoting genetics in non-alcoholic fatty liver disease: Combined risk score through polymorphisms and clinical variables , 2018, World journal of gastroenterology.

[4]  H. Cao,et al.  PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease , 2018, World journal of clinical cases.

[5]  Z. Yao,et al.  Non-alcoholic fatty liver disease: a narrative review of genetics , 2018, Journal of biomedical research.

[6]  Yuya Seko,et al.  The genetic backgrounds in nonalcoholic fatty liver disease , 2018, Clinical Journal of Gastroenterology.

[7]  T. Kawaguchi,et al.  Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers , 2018, PloS one.

[8]  M. Imamura,et al.  Influence of the rs738409 polymorphism in patatin‐like phospholipase 3 on the treatment efficacy of non‐alcoholic fatty liver disease with type 2 diabetes mellitus , 2016, Hepatology research : the official journal of the Japan Society of Hepatology.

[9]  S. Petta,et al.  Genetic background in nonalcoholic fatty liver disease: A comprehensive review. , 2015, World journal of gastroenterology.

[10]  M. Moriguchi,et al.  Serum alanine aminotransferase predicts the histological course of non‐alcoholic steatohepatitis in Japanese patients , 2015, Hepatology research : the official journal of the Japan Society of Hepatology.

[11]  E. Bjornsson,et al.  Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. , 2015, Gastroenterology.

[12]  D. Reddy,et al.  The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis. , 2015, Journal of clinical and experimental hepatology.

[13]  Zhibin Li,et al.  Serum Alanine Aminotransferase Independently Correlates with Intrahepatic Triglyceride Contents in Obese Subjects , 2014, Digestive Diseases and Sciences.

[14]  T. Saibara,et al.  Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients , 2014, Journal of Gastroenterology.

[15]  P. Bedossa,et al.  A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. , 2013, Journal of hepatology.

[16]  Luca Valenti,et al.  Genetic Predisposition in NAFLD and NASH: Impact on Severity of Liver Disease and Response to Treatment , 2013, Current pharmaceutical design.

[17]  B. Neuschwander‐Tetri,et al.  Vitamin E and changes in serum alanine aminotransferase levels in patients with non‐alcoholic steatohepatitis , 2013, Alimentary pharmacology & therapeutics.

[18]  T. Saibara,et al.  Noninvasive scoring systems in patients with nonalcoholic fatty liver disease with normal alanine aminotransferase levels , 2013, Journal of Gastroenterology.

[19]  T. Saibara,et al.  Genetic Polymorphisms of the Human PNPLA3 Gene Are Strongly Associated with Severity of Non-Alcoholic Fatty Liver Disease in Japanese , 2012, PloS one.

[20]  M. Taniai,et al.  Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease, and chronic liver disease of unknown etiology: report of the nationwide survey , 2011, Journal of Gastroenterology.

[21]  A. Sekine,et al.  Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease , 2010, BMC Medical Genetics.

[22]  T. Liang,et al.  The association of genetic variability in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease , 2010, Hepatology.

[23]  Vincent Wai-Sun Wong,et al.  Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years , 2010, Gut.

[24]  Hirokazu Takahashi,et al.  The pathological role of visceral fat accumulation in steatosis, inflammation, and progression of nonalcoholic fatty liver disease , 2010, Journal of Gastroenterology.

[25]  S. Caldwell,et al.  Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. , 2009, Journal of hepatology.

[26]  Alexander Pertsemlidis,et al.  Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease , 2008, Nature Genetics.

[27]  Khean-Lee Goh,et al.  How common is non‐alcoholic fatty liver disease in the Asia–Pacific region and are there local differences? , 2007, Journal of gastroenterology and hepatology.

[28]  M. Taniai,et al.  Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. , 2007, Journal of hepatology.

[29]  M. Holmqvist,et al.  Long‐term follow‐up of patients with NAFLD and elevated liver enzymes , 2006, Hepatology.

[30]  T. Omatsu,et al.  The Metabolic Syndrome as a Predictor of Nonalcoholic Fatty Liver Disease , 2006, Annals of Internal Medicine.

[31]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[32]  S. Sanderson,et al.  The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. , 2005, Journal of hepatology.

[33]  E. Fassio,et al.  Natural history of nonalcoholic steathepatitis: A longitudinal study of repeat liver biopsies , 2004, Hepatology.

[34]  Shohei Matsuzaki,et al.  Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background , 2003, Journal of Gastroenterology.

[35]  Yusuke Nakamura,et al.  A high-throughput SNP typing system for genome-wide association studies , 2001, Journal of Human Genetics.

[36]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions , 1999, American Journal of Gastroenterology.

[37]  Z. Younossi,et al.  Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. , 1999, Gastroenterology.

[38]  C. Day,et al.  Non-alcoholic steatohepatitis: another disease of affluence , 1999, The Lancet.

[39]  L Dalla Palma,et al.  Noninvasive in vivo quantitative assessment of fat content in human liver. , 1997, Journal of hepatology.

[40]  M. Bennett,et al.  The natural history of nonalcoholic fatty liver: A follow‐up study , 1995, Hepatology.