Intestinal Microbiota, Lipids, and the Pathogenesis of Intestinal Failure-Associated Liver Disease.

ntestinal failure (IF) is considered the end result of gastrointestinal disorders in which functional intestinal mass is inadequate to promote adequate growth, hydration, and electrolyte balance. Today, a substantial number of infants and children with IF, caused by short bowel syndrome, necrotizing enterocolitis, gastroschisis, intestinal atresias, motility disorders, and genetic enterocyte transport defects, depend on long-term parenteral nutrition (PN) for survival and the promotion of normal growth and development. PN–associated cholestasis (PNAC), which refers to the development of conjugated hyperbilirubinemia and impaired bile flow, implies that PN itself is the predominant factor responsible for liver injury. A recent understanding of the various factors that cause liver injury in patients receiving PN, however, has led to the broader descriptive term of IF– associated liver disease (IFALD), which replaces the previous term PN–associated liver disease (PNALD). IFALD is defined as cholestasis and progressive biliary cirrhosis in the setting of PN in a patient with underlying intestinal disease, resection, or dysfunction, if other specific causes of liver injury have been excluded. It is in these patients that the most severe, progressive, and sometimes-fatal phenotypes of PNAC develop; hence, IFALD has become the leading indication for intestinal and multivisceral transplantation in children. In addition to progressive biliary cirrhosis and portal hypertension, hepatocellular carcinoma has been reported as a rare complication in children with liver cirrhosis secondary to long-term PN. Advanced IFALD is one of the most significant risk factors associated with mortality in infants on long-term PN. There are several recent reviews on the pathogenic mechanisms predisposing infants to IFALD and various strategies to prevent or reverse established IFALD. Prematurity and small for gestational age, length of bowel remnant in those who had bowel resection, lack of enteral feeding, duration of PN, recurrent sepsis, protein undernutrition, and an