Potential conflict of interest: Dr. Tillmann owns stock in AbbVie, Abbott, and Gilead.
Steatohepatitis/Metabolic Liver Disease
Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease
Article first published online: 13 DEC 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 59, Issue 2, pages 471–482, February 2014
How to Cite
Moylan, C. A., Pang, H., Dellinger, A., Suzuki, A., Garrett, M. E., Guy, C. D., Murphy, S. K., Ashley-Koch, A. E., Choi, S. S., Michelotti, G. A., Hampton, D. D., Chen, Y., Tillmann, H. L., Hauser, M. A., Abdelmalek, M. F. and Diehl, A. M. (2014), Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatology, 59: 471–482. doi: 10.1002/hep.26661
The majority of this work was supported through an American Recovery and Reinvestment Act (ARRA) grant from the National Institute on Alcohol Abuse and Alcoholism (5RC2 AA019399; A.M.D., principal investigator). Drs. Diehl and Abdelmalek received funding support from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK; grant no.: U01-DK57149). Dr. Abdelmalek was supported by a NIH/NIDDK K23 Career Development Award (K23-DK062116).
- Issue published online: 29 JAN 2014
- Article first published online: 13 DEC 2013
- Accepted manuscript online: 2 AUG 2013 06:46AM EST
- Manuscript Accepted: 26 JUL 2013
- Manuscript Received: 26 MAY 2013
Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into subpopulations at high- versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, “mild” NAFLD patients (fibrosis stage 0-1; n = 40) and high-risk, “severe” NAFLD patients (fibrosis stage 3-4; n = 32). Findings were validated in a second, independent cohort and confirmed by real-time polymerase chain reaction and immunohistochemistry (IHC). As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64-gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20-gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and IHC confirmed deregulation of metabolic and regenerative pathways in severe NAFLD and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer. Conclusion: By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality. (Hepatology 2014;59:471–482)