The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes fatty liver (NAFL) and steatohepatitis (NASH), which can progress to cirrhosis in up to 20% of NASH patients. Bile acids (BA) are linked to the pathogenesis and therapy of NASH. We (1) characterized the plasma BA profile in biopsy-proven NAFL and NASH and compared to controls and (2) related the plasma BA profile to liver histologic features, disease activity, and fibrosis. Liquid chromatography/mass spectrometry quantified BAs. Descriptive statistics, paired and multiple group comparisons, and regression analyses were performed. Of 86 patients (24 controls, 25 NAFL, and 37 NASH; mean age 51.8 years and body mass index 31.9 kg/m2 ), 66% were women. Increased total primary BAs and decreased secondary BAs (both P < 0.05) characterized NASH. Total conjugated primary BAs were significantly higher in NASH versus NAFL (P = 0.047) and versus controls (P < 0.0001). NASH had higher conjugated to unconjugated chenodeoxycholate (P = 0.04), cholate (P = 0.0004), and total primary BAs (P < 0.0001). The total cholate to chenodeoxycholate ratio was significantly higher in NAFLD without (P = 0.005) and with (P = 0.02) diabetes. Increased key BAs were associated with higher grades of steatosis (taurocholate), lobular (glycocholate) and portal inflammation (taurolithocholate), and hepatocyte ballooning (taurocholate). Conjugated cholate and taurocholate directly and secondary to primary BA ratio inversely correlated to NAFLD activity score. A higher ratio of total secondary to primary BA decreased (odds ratio, 0.57; P = 0.004) and higher conjugated cholate increased the likelihood of significant fibrosis (F≥2) (P = 0.007). Conclusion: NAFLD is associated with significantly altered circulating BA composition, likely unaffected by type 2 diabetes, and correlated with histological features of NASH; these observations provide the foundation for future hypothesis-driven studies of specific effects of BAs on specific aspects of NASH. (Hepatology 2018;67:534-548).
The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes fatty liver (NAFL) and steatohepatitis (NASH), which can progress to cirrhosis in up to 20% of NASHpatients. Bile acids (BA) are linked to the pathogenesis and therapy of NASH. We (1) characterized the plasma BA profile in biopsy-proven NAFL and NASH and compared to controls and (2) related the plasma BA profile to liver histologic features, disease activity, and fibrosis. Liquid chromatography/mass spectrometry quantified BAs. Descriptive statistics, paired and multiple group comparisons, and regression analyses were performed. Of 86 patients (24 controls, 25 NAFL, and 37 NASH; mean age 51.8 years and body mass index 31.9 kg/m2 ), 66% were women. Increased total primary BAs and decreased secondary BAs (both P < 0.05) characterized NASH. Total conjugated primary BAs were significantly higher in NASH versus NAFL (P = 0.047) and versus controls (P < 0.0001). NASH had higher conjugated to unconjugated chenodeoxycholate (P = 0.04), cholate (P = 0.0004), and total primary BAs (P < 0.0001). The total cholate to chenodeoxycholate ratio was significantly higher in NAFLD without (P = 0.005) and with (P = 0.02) diabetes. Increased key BAs were associated with higher grades of steatosis (taurocholate), lobular (glycocholate) and portal inflammation (taurolithocholate), and hepatocyte ballooning (taurocholate). Conjugated cholate and taurocholate directly and secondary to primary BA ratio inversely correlated to NAFLD activity score. A higher ratio of total secondary to primary BA decreased (odds ratio, 0.57; P = 0.004) and higher conjugated cholate increased the likelihood of significant fibrosis (F≥2) (P = 0.007). Conclusion: NAFLD is associated with significantly altered circulating BA composition, likely unaffected by type 2 diabetes, and correlated with histological features of NASH; these observations provide the foundation for future hypothesis-driven studies of specific effects of BAs on specific aspects of NASH. (Hepatology 2018;67:534-548).
Authors: Stephen Caldwell; Yoshihiro Ikura; Daniela Dias; Kosuke Isomoto; Akito Yabu; Christopher Moskaluk; Patcharin Pramoonjago; Winsor Simmons; Harriet Scruggs; Nicholas Rosenbaum; Timothy Wilkinson; Patsy Toms; Curtis K Argo; Abdullah M S Al-Osaimi; Jan A Redick Journal: J Hepatol Date: 2010-06-25 Impact factor: 25.083
Authors: Kerry L Donnelly; Coleman I Smith; Sarah J Schwarzenberg; Jose Jessurun; Mark D Boldt; Elizabeth J Parks Journal: J Clin Invest Date: 2005-05 Impact factor: 14.808
Authors: M Makishima; A Y Okamoto; J J Repa; H Tu; R M Learned; A Luk; M V Hull; K D Lustig; D J Mangelsdorf; B Shan Journal: Science Date: 1999-05-21 Impact factor: 47.728
Authors: Robert J Wong; Maria Aguilar; Ramsey Cheung; Ryan B Perumpail; Stephen A Harrison; Zobair M Younossi; Aijaz Ahmed Journal: Gastroenterology Date: 2014-11-25 Impact factor: 22.682
Authors: Sunder Mudaliar; Robert R Henry; Arun J Sanyal; Linda Morrow; Hanns-Ulrich Marschall; Mark Kipnes; Luciano Adorini; Cathi I Sciacca; Paul Clopton; Erin Castelloe; Paul Dillon; Mark Pruzanski; David Shapiro Journal: Gastroenterology Date: 2013-05-30 Impact factor: 22.682
Authors: Georg Zeller; Julien Tap; Anita Y Voigt; Shinichi Sunagawa; Jens Roat Kultima; Paul I Costea; Aurélien Amiot; Jürgen Böhm; Francesco Brunetti; Nina Habermann; Rajna Hercog; Moritz Koch; Alain Luciani; Daniel R Mende; Martin A Schneider; Petra Schrotz-King; Christophe Tournigand; Jeanne Tran Van Nhieu; Takuji Yamada; Jürgen Zimmermann; Vladimir Benes; Matthias Kloor; Cornelia M Ulrich; Magnus von Knebel Doeberitz; Iradj Sobhani; Peer Bork Journal: Mol Syst Biol Date: 2014-11-28 Impact factor: 11.429
Authors: Stephanie J Shiffka; Jace W Jones; Linhao Li; Ann M Farese; Thomas J MacVittie; Hongbing Wang; Peter W Swaan; Maureen A Kane Journal: J Lipid Res Date: 2020-07-22 Impact factor: 5.922
Authors: Cyrielle Caussy; Veeral H Ajmera; Puneet Puri; Cynthia Li-Shin Hsu; Shirin Bassirian; Mania Mgdsyan; Seema Singh; Claire Faulkner; Mark A Valasek; Emily Rizo; Lisa Richards; David A Brenner; Claude B Sirlin; Arun J Sanyal; Rohit Loomba Journal: Gut Date: 2018-12-19 Impact factor: 23.059
Authors: Gabriella V Hernandez; Victoria A Smith; Megan Melnyk; Matthew A Burd; Kimberly A Sprayberry; Mark S Edwards; Daniel G Peterson; Darin C Bennet; Rob K Fanter; Daniel A Columbus; Juan P Steibel; Hunter Glanz; Chad Immoos; Margaret S Rice; Tasha M Santiago-Rodriguez; Jason Blank; Jennifer J VanderKelen; Christopher L Kitts; Brian D Piccolo; Michael R La Frano; Douglas G Burrin; Magdalena Maj; Rodrigo Manjarin Journal: Am J Physiol Gastrointest Liver Physiol Date: 2020-01-31 Impact factor: 4.052