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

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Intestinal failure (IF) is considered the end result of gastrointestinal disorders in which functional intestinal mass is inadequate to promote adequate growth, hydration, and electrolye balance.1 Today, a substantial number of infants and children with IF, caused by short bowel syndrome (SBS), necrotizing enterocolitis (NEC), gastroschisis, intestinal atresias, motlity disorders and genetic enterocyte transport defects, depend upon long term parenteral nutrition (PN) for survival and the promotion of normal growth and development. PN-associated cholestasis (PNAC), referring to the development of conjugated hyperbilirubinemia and impaired bile flow, implies that PN itself is the predominant factor responsible for liver injury.2 However, recent understanding of the various factors causing liver injury in patients receiving PN has led to the broader descriptive term of IF–associated liver disease (IFALD),3 replacing 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.4 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 multi-visceral 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.5 Advanced IFALD is one of the most significant risk factors associated with mortality in infants on long-term PN.6, 7 There are several recent reviews on the pathogenic mechanisms predisosing to IFALD and various strategies to prevent or reverse established IFALD.2, 4, 8-10 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 under nutrition and excess of intravenous carbohydrate load have been considered as important factors for the development IFALD.3 Mechanisms receiving the most recent attention include the role of omega(ω)-6 polyunsaturated fatty acids (PUFA) and plant sterols found in the intravenous lipid emulsions (ILEs),8 bacterial overgrowth and microbiome dysbiosis of the small intestine,11 the role of bacteremia and fungemia related to microbial translocation across the intestinal barrier and central line associated blood stream infections (CLABSI), and increased intestinal permeability leading to absorption of bacterial products from injured intestine inducing innate immune responses in the liver.12, 13 The purpose of the present review is to discuss the latest understanding of the role of various ILEs and intestinal microbial dysbiosis.14, 15