[11, 15] Transition from olive-oil–based PN lipid to fish-oil–based Gefitinib clinical trial PN lipid emulsion may result in reversal of biochemical indicators of cholestasis.[37] However, 2 patients with persisting liver fibrosis 3 and 11 months after transition to fish-oil–based PN have been reported on.[38] In this study, we found abnormal liver histology, including mainly fibrosis (Metavir stage 2 in 50%) and steatosis with occasional portal inflammation, in 77% of patients after weaning off PN an average of 8.8 years before. Interestingly,

degree of liver fibrosis was comparable during and after weaning off PN, although the weak inverse correlation between Metavir stage and time after weaning off PN suggest that some resolution of fibrosis may occur over time. Bacterial overgrowth, epithelial changes, and impaired local immunity of the small intestine check details may provide potential mechanisms causing and maintaining liver injury in IFALD, both during and after weaning off PN.[39] In a mouse model of IF, PN-induced increase in intestinal permeability promotes Toll-like receptor 4–dependent Kupffer cell activation and liver injury, presumably caused by bacterial translocation.[42] In short bowel syndrome, loss of barrier function of the ileocecal valve, adaptation-induced bowel dilatation, and impaired motility after massive intestinal

resection are known risk factors for bacterial overgrowth.[41] Together with increased intestinal permeability,[43] these alterations may promote bacterial translocation and subsequent liver injury also in IF patients.[44] Here, the number of blood culture-positive septic episodes, reflecting both central venous catheter- and bacterial translocation-related septic episodes, correlated positively with liver fibrosis and chronic cholestasis (periportal CK7 staining). Moreover,

the patients with the shortest Sitaxentan remaining small bowel and those without an ileocecal valve had the most advanced liver fibrosis stage. The exact mechanism of liver protection exerted by the small intestine is most likely multifactorial, but may involve enterohepatic circulation of bile acids.[45] Short length of the remaining small intestine also reflects decreased enteral absorption with increased and prolonged PN requirements. Accordingly, duration of PN and extensive small intestinal resection positively correlated with both fibrosis and steatosis. The fact that liver fibrosis stage was inversely related to young starting age of PN emphasizes the vulnerability of newborn liver function. In a multivariate analysis, age-adjusted small bowel length, portal inflammation, and absence of an ileocecal valve were the most significant predictors of Metavir fibrosis stage. Although APRI correlated with histological liver fibrosis, any of the conventional liver function tests were off normal limits only in 63% of patients on PN and in 18% of patients weaned off PN, whereas liver US was abnormal only in 4 patients.