Intestinal Failure-Associated Liver Disease

Abstract

Intestinal failure (IF)-associated liver disease (IFALD) refers to hepatobiliary dysfunction, which arises during parenteral nutrition (PN) delivered for compromised bowel function and related intestinal failure. Clinical hallmark of IFALD is cholestasis, which may rapidly progress to biliary cirrhosis and liver failure especially in newborns with immature liver function. Initial histological changes are dominated by cholestasis and inflammation, which are largely replaced by fibrosis and steatosis with prolonged duration of PN and increasing age. Abnormal liver fibrosis and steatosis persist after weaning of PN in a significant proportion of patients. Pathogenesis of IFALD is complex and multifactorial including both hepatotoxic effects of PN and disturbed intestinal function. All PN lipids excluding fish oil-derived emulsions contain plant sterols, which in experimental studies activate Kupffer cells through toll-like receptor 4 signaling and attenuate bile transporter expression synergistically with increased lipopolysaccharide permeability in mice. Plant sterols correlate with biochemical and histological signs of liver injury in children with IF, who also display intestinal barrier dysfunction with overabundance of lipopolysaccharide producing Proteobacteria in their intestinal microbiota in association with intestinal inflammation and elevated serum proinflammatory cytokines. Reduction of farnesoid X receptor induction and fibroblast growth factor 19 secretion due to extensive distal resection and altered bile acid metabolism may contribute to maintenance of liver injury also after weaning off PN. No specific therapy for IFALD is currently available. Multidisciplinary preventive measures include limitation of PN lipid load and plant sterol content, while maintaining balanced fatty acid profile and avoidance of systemic bacteremia by dedicated central venous catheter care and surgical treatment of obstructive short bowel pathology predisposing to bacterial overgrowth.