Intestinal microbiota composition was associated with liver steatosis in IF and better predicted steatosis than duration of PN or length of the remaining intestine. Our results may be explained by a model in which steatosis is initiated during PN in response to proinflammatory lipopolysaccharides produced by Proteobacteria and progresses after weaning off PN, as the L plantarum group Lactobacilli becomes dominant and affects lipid metabolism by altering bile acid signaling.
The aim of this study was to evaluate the long-term effects of pediatric intestinal failure (IF) on liver histology. Altogether, 38 IF patients (median age: 7.2 years; range, 0.2-27) underwent liver biopsy, gastroscopy, abdominal ultrasound, and laboratory tests. Sixteen patients were on parenteral nutrition (PN) after 74 PN months (range, 2.5-204). Twentytwo had weaned off PN 8.8 years (range, 0.3-27) earlier, after 35 PN months (range,. Fifteen transplant donor livers served as controls. Abnormal liver histology was found in 94% of patients on PN and 77% of patients weaned off PN (P 5 0.370). During PN, liver histology weighted with cholestasis (38% of patients on PN versus 0% of patients weaned off PN; P 5 0.003) and portal inflammation (38% versus 9%; P 5 0.050) were found. Fibrosis (88% versus 64%; P 5 0. ; P 5 0.037) were significantly higher during than after weaning off PN. Esophageal varices were encountered in 1 patient after weaning off PN. Metavir stage was associated with small bowel length (r 5 20.486; P 5 0.002) and number of septic episodes (r 5 0.480; P 5 0.002). In a multivariate analysis, age-adjusted small bowel length (ß 5 20.533; P 5 0.001), portal inflammation (ß 5 0.291; P 5 0.030), and absence of an ileocecal valve (ß 5 0.267; P 5 0.048) were predictive for fibrosis stage. Conclusion: Despite resolution of cholestasis and portal inflammation, significant liver fibrosis and steatosis persist after weaning off PN. Extensive small intestinal resection was the major predictor for liver fibrosis stage. (HEPATOLOGY 2013;58:729-738)
Increased serum stigmasterol and avenasterol concentrations parallel the portal inflammation and cholestasis during PN, thereby reinforcing their contribution to IFALD. A bile acid malabsorption-driven increase in cholesterol synthesis underpins persistent liver steatosis after weaning off PN. Serum cholestanol reflects liver injury in IF patients.
Necrotizing enterocolitis (NEC) is a devastating neonatal disease characterized by acute intestinal injury. Intestinal stem cell (ISC) renewal is required for gut regeneration in response to acute injury. The Wnt/β-catenin pathway is essential for intestinal renewal and ISC maintenance. We found that ISC expression, Wnt activity and intestinal regeneration were all decreased in both mice with experimental NEC and in infants with acute active NEC. Moreover, intestinal organoids derived from NEC-injured intestine of both mice and humans failed to maintain proliferation and presented more differentiation. Administration of Wnt7b reversed these changes and promoted growth of intestinal organoids. Additionally, administration of exogenous Wnt7b rescued intestinal injury, restored ISC, and reestablished intestinal epithelial homeostasis in mice with NEC. Our findings demonstrate that during NEC, Wnt/β-catenin signaling is decreased, ISC activity is impaired, and intestinal regeneration is defective. Administration of Wnt resulted in the maintenance of intestinal epithelial homeostasis and avoidance of NEC intestinal injury.
Among children with IF, parenteral PSs accumulate in the liver, reflect their increased serum levels, and relate with biochemical liver injury, portal inflammation, and liver fibrosis, thus supporting their role in promoting liver damage.
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