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Liver Inflammation Relates to Decreased Canalicular Bile Transporter Expression in Pediatric Onset Intestinal Failure
Annika Mutanen1, Jouko Lohi2, Päivi Heikkilä2
1Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Insights
Parenteral nutrition (PN) in pediatric intestinal failure (IF) can cause liver inflammation and injury by altering bile transporter gene expression. This study reveals molecular mechanisms linking PN to liver damage in IF patients.
Area of Science:
- Hepatology
- Pediatric Gastroenterology
- Molecular Biology
Background:
- Liver disease is a significant complication of parenteral nutrition (PN) for intestinal failure (IF).
- The precise molecular mechanisms driving liver injury in pediatric IF patients receiving PN are not fully understood.
- Investigating these mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To explore the molecular underpinnings of liver injury in pediatric patients with intestinal failure (IF) receiving parenteral nutrition (PN).
- To identify key molecular players and pathways involved in PN-associated liver disease (PNALD) in this vulnerable population.
Main Methods:
- Examined liver expression of bile acid and sterol transporters (ABCB4, ABCB11, ABCG5/8) and their regulators (LXR, FXR).
- Assessed pro-inflammatory cytokines (IL6, TNF) in relation to liver injury markers, PN status, and serum biomarkers.
- Compared gene and protein expression between patients currently on PN and those weaned off PN.
Main Results:
- Patients on current PN exhibited more severe liver injury, characterized by portal inflammation, cholestasis, and fibrosis, compared to those weaned off PN.
- Portal inflammation correlated with increased IL6/TNF expression and suppressed FXR signaling, including reduced expression of bile transporter genes (ABCB4, ABCB11).
- PN, elevated serum plant sterols, and reduced enterocyte mass (indicated by citrulline) predicted portal inflammation.
Conclusions:
- In pediatric IF, PN combined with intestinal compromise promotes liver inflammation.
- This inflammation is linked to progressive liver injury and reduced expression of essential canalicular bile transporters.
- Understanding these pathways is vital for managing PNALD in pediatric IF.
Objective:
Although liver disease is a major complication of parenteral nutrition (PN) for intestinal failure (IF), its pathogenesis remains unclear. We investigated potential molecular mechanisms of liver injury in pediatric onset IF.
Methods:
Liver expression of canalicular phospholipid (ABCB4), bile acid (ABCB11), and sterol (ABCG5/8) transporters, their upstream regulators LXR and FXR as well as pro-inflammatory cytokines interleukin-6 (IL6) and tumor necrosis factor (TNF) were investigated among patients with IF [age median 3.8 (IQR 1.2 to 11)] in relation to biochemical and histologic liver injury, PN, serum plant sterols, fibroblast growth factor 19, and α-tocopherol.
Results:
Patients receiving PN currently (n = 18) showed more advanced liver injury than patients after weaning off PN (n = 30). Histologic portal inflammation strongly segregated PN-dependent (44%) from weaned off patients (3%, P = 0.001) and coupled with progression of cholestasis and liver fibrosis. Patients with portal inflammation demonstrated markedly induced liver RNA expression of IL6 and TNF, repression of FXR and its canalicular bile transporter target gene RNA expression, including ABCB4 and ABCB11 as well as decreased protein expression of ABCB11 and ABCB4. Furthermore, upregulation of LXR and ABCG5/8 RNA expression was suppressed in patients with portal inflammation. Current PN, increased serum levels of plant sterols stigmasterol, avenasterol, and sitosterol along with serum citrulline, a marker of enterocyte mass, predicted portal inflammation.
Conclusions:
In pediatric onset IF, current PN delivery synergistically with intestinal compromise promote liver inflammation, which associates with progression of biochemical and histologic liver injury, while reducing expression of canalicular bile transporters.
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