Table of Contents
Advances in Hepatology
Volume 2014, Article ID 621380, 7 pages
http://dx.doi.org/10.1155/2014/621380
Review Article

Newly Identified Mechanisms of Total Parenteral Nutrition Related Liver Injury

1St. Louis University School of Medicine, Cardinal Glennon Children’s Medical Center, 1465 South Grand Boulevard, St. Louis, MO 63104, USA
2Department of Pediatrics, Saint Louis University, SSM Cardinal Glennon Hospital, 1465 South Grand Boulevard, St. Louis, MO 63104, USA

Received 4 March 2014; Accepted 18 May 2014; Published 25 June 2014

Academic Editor: Sharon DeMorrow

Copyright © 2014 Ajay Kumar Jain and Jeffrey H. Teckman. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Total parenteral nutrition (TPN), a lifesaving therapy, involves providing nutrition by bypassing the gut. Unfortunately it is associated with significant complications including gut atrophy and parenteral nutrition associated liver disease (PNALD). PNALD includes steatosis, cholestasis, disrupted glucose metabolism, disrupted lipid metabolism, cirrhosis, and liver failure. The etiopathogenesis remains poorly defined; however, an altered enterohepatic circulation, disrupting nuclear receptor signaling, is emerging as a promising mechanism. Rodent models and our piglet TPN model have shown that, during regular feeding, bile acids activate farnesoid X receptor (FXR) in the gut and enhance fibroblast growth factor 19 (FGF19) level. FGF19 regulates bile acid, lipid, and glucose metabolism. We noted reduced FGF19 with TPN use and substantial improvement in FGF19, bilirubin, and metabolic profiles with the FXR agonist chenodeoxycholic acid (CDCA). Additionally, CDCA caused gut growth and enhanced expression of glucagon like peptides (GLPs). GLPs regulate gut trophic effects, insulin, glucose homeostasis, and hepatic steatosis. GLP secretion is regulated by the CDCA activated receptor TGR5. This leads to an important conclusion that, in addition to a disrupted FXR-FGF19 axis, a disrupted TGR5-GLP axis may contribute to TPN related pathologies. Thus modulators of FXR-FGF19 and the TGR5-GLP axis could help bring forward novel treatment strategies.