New Insights Into Intestinal Failure-Associated Liver Disease in Children

Abstract

Development of intestinal failure-associated liver disease (IFALD) is a common complication of long-term parenteral nutrition (PN) in children and adults. The molecular and cellular mechanisms and the phases of IFALD are now being delineated. Components of PN lipid emulsions, including plant sterols, interact with hepatic innate immune activation promoted by products of gut bacterial overgrowth/dysbiosis and altered intestinal barrier function (gut-liver axis) and by episodes of sepsis to cause cholestasis and IFALD. New therapeutic strategies, including modifications of intravenous lipid emulsions to reduce pro-inflammatory fatty acids and plant sterol content, can lower the risk of IFALD, reverse cholestasis, and reduce complications, although the significance of persisting hepatic fibrosis is unknown. This review will provide an update on advances in the pathogenesis of IFALD, newer therapeutic and preventative strategies, and challenges that confront managing patients with IFALD.

FIG. 1.

Clinical phases 1 (cholestasis and inflammation) and 2 (fibrosis and steatosis) of IFALD with corresponding photomicrographs of liver histology in pediatric patients with IFALD. Phase 1 IFALD (A,B) is characterized by an inflammatory, cholestatic lesion that progresses relatively rapidly to fibrosis. Increased production of IL-1β and TNFα are accompanied by down-regulation of BSEP, MRP2, and ABCG5/G8, caused by combined effect of PN-derived phytosterols and LPSs and other PAMPs absorbed from the hyperpermeable bowel.^(26,27) Phase 2 IFALD (C,D) with periportal fibrosis, but absent inflammation and cholestasis. Phase 2 IFALD follows parenteral nutrition discontinuation in which persistent and perhaps progressive fibrosis and steatosis remain present. This phase is characterized by increased liver immunohistochemical staining for smooth muscle actin, a marker of hepatic stellate cells, and increased collagen gene expression with accompanying up-regulation of proinflammatory and profibrotic cytokines and growth factors (IL-1α, IL-1β, EGF, adhesion molecule integrin-β6, and MMP9) in the liver.^(26,27,30) This transcriptional profile suggests that altered intestinal barrier function and microbial dysbiosis that persist even after PN discontinuation may be the primary drivers of persistent HF (original magnification: panel A, H&E ×4; panel B, H&E ×10; panel C, H&E ×4; panel D, trichrome ×4). Abbreviations: Coll1, collagen 1; EGF, epithelial growth factor; H&E, hematoxylin and eosin; MMP9, matrix metalloproteinase 9; α-SMA, alpha-smooth muscle actin; TNFα, tumor necrosis factor alpha.

FIG. 2.

Factors implicated in the pathogenesis and progression (red headings) of liver injury leading to IFALD and those associated with improved outcomes (green headings) in patients who are dependent on PN. Risk factors can be categorized as either patient related or PN related. Patient risk factors include presence of small intestinal bacterial overgrowth, prematurity, recurrent episodes of sepsis, paucity of enteral intake, dilated small bowel, and interrupted enterohepatic circulation secondary to surgical interventions. PN-related risk factors include the type and amount of ILEs, lack of antioxidants in lipid emulsions, micronutrient imbalances, duration of infusion period, and lack of PN cycling. Clinical evidence also points to an association between intestinal microbiota and IFALD. In patients with IF and PN dependence, presence of hepatic steatosis was associated with fecal microbial dysbiosis exemplified by reduced microbial diversity and richness and increased predominance of Proteobacteria, specifically Enterobacteriaciae, which are rich in LPSs (endotoxin).^(34,35) Microbial dysbiosis has also been shown to be associated with lack of enteral feedings and increased intestinal permeability in a mouse model of PNALD.⁽⁶⁴⁾

FIG. 3.

Proposed model of IFALD pathogenesis. Intestinal disruption, including increased mucosal permeability, intestinal injury, small bowel bacterial overgrowth, and dysbiosis, leads to hepatic macrophage activation through absorbed LPS and other PAMPs and bacterial translocation. Following LPS absorption into the portal circulation, TLR4 is engaged, leading to macrophage activation and subsequent cytokine (primarily IL-1β, IL-6, and TNFα) production and secretion.⁽⁶⁴⁾ IL-1β engages hepatocyte IL1 receptors and, through NFκB signaling, down-regulates LXR and canalicular ABCG5/G8, which promotes hepatocyte accumulation of intravenously infused phytosterols.^(27,30,31) Reduced ileal enterocyte production of FGF19, attributable to ileal resection or disease, leads to less engagement of FGFR4 receptor on hepatocytes and releases CYP7A1 to catalyze synthesis of more potentially hepatotoxic bile acids.⁽³⁶⁾ The combined effect of high levels of retained stigmasterol and macrophage-derived IL-1β/NFκB signaling in the hepatocyte down-regulates FXR, BSEP, and MRP2 and leads to bile acid retention and cholestatic injury.^(26,27) Abbreviations; CASP1, caspase-1; LXR, liver X receptor; TNFα, tumor necrosis factor alpha.