Pathogenesis and Management of Intestinal Failure-Associated Liver Disease

Abstract

Long-term parenteral nutrition (PN) has considerably improved the management of intestinal failure (IF) in children and adults, particularly those with short bowel syndrome; however, it carries a significant risk of hepatotoxicity, specifically, intestinal failure-associated liver disease (IFALD), also known as PN-associated liver disease. This review provides an update on the latest understanding of IFALD pathogenesis, emerging therapies, and ongoing challenges in the management of this complication. A number of factors are associated with the development of IFALD. PN lipid emulsions, phytosterol exposure, bacterial dysbiosis, an altered gut-liver axis, and episodes of sepsis disrupt bile acid homeostasis and promote liver inflammation in the active phase of IFALD, favoring the development of PN-associated cholestasis (PNAC) and the more chronic form of steatohepatitis with fibrosis. Based on the identification of pathophysiological pathways, potential therapies are being studied in preclinical and clinical trials, including lipid emulsion modifications; targeted therapies such as Farnesoid X receptor (FXR) and liver receptor homolog 1 (LRH-1) agonists, tumor necrosis factor inhibitors, glucagon-like peptide-2 analogs; microbiome modulation; and supplementation with choline and antioxidants. In conclusion, the pathogenesis of IFALD is complex, and PN dependence and liver injury remain challenging, particularly in patients with IF who cannot advance to enteral nutrition and be weaned off PN.

Fig. 1

Liver histology of the acute/active phase of IFALD (cholestasis and inflammation). ( A ) The hepatic trabecular architecture shows focal pseudoacinar transformation around intracanalicular bile plugs, primarily in a lobular and pericentral distribution with associated extramedullary hematopoiesis. (hematoxylin–eosin, original magnification 40×). ( B ) A portal area shows a bile duct plug (arrow). (hematoxylin–eosin, original magnification 100×). ( C ) No bridging fibrosis is seen. (trichrome, original magnification 40×). ( D ) No periportal, central vein, or sinusoidal fibrosis is seen. (trichrome, original magnification 100×). IFALD, intestinal failure-associated liver disease.

Fig. 2

Liver histology of the chronic phase of IFALD (steatosis and fibrosis). ( A ) The hepatic architecture is distorted with scattered macrovesicular steatosis, primarily in a lobular and pericentral distribution (hematoxylin–eosin, original magnification 100×). ( B ) Hepatocyte swelling is evident with scattered macrovesicular steatosis. Bile ductular reaction is present at the periphery of the portal areas. No cholestasis is evident within the hepatocytes, canaliculi, or bile ducts. (hematoxylin–eosin, original magnification 200×). ( C ) Fibrosis is present diffusely with delicate bridging but without cirrhosis. (trichrome, original magnification 40×). ( D ) Marked periportal and pericentral fibrosis is highlighted with associated sinusoidal fibrosis and portal-central bridging. (trichrome, original magnification 200×). IFALD, intestinal failure-associated liver disease.

Fig. 3

Factors contributing to the pathogenesis of IFALD. Factors contributing to the pathogenesis of IFALD include patient-related, infectious, surgical, and parenteral nutrient factors. Patient-related factors, such as gut and liver prematurity, intestinal inflammation, increased gut permeability, dilated small bowel, and genetic predisposition increase susceptibility to liver injury. Infectious factors, including small intestinal bacterial overgrowth, recurrent sepsis, and intestinal dysbiosis, disrupt the intestinal microbiome, promoting macrophage activation, hepatic inflammation, and cholestasis. Surgical interventions, such as end-jejunostomy and ileal resection leading to short bowel syndrome types 1 and 2, respectively, disrupt the enterohepatic recirculation of bile acids and the gut–liver axis, leading to activation of hepatic inflammatory pathways and alterations in bile acid metabolism. Lastly, PN-related factors, including the type and amount of intravenous lipid emulsions (ILEs), infusion duration and frequency, PN cycling, antioxidant balance, and micronutrient deficiencies (e.g., choline, taurine, glutamine) are associated with IFALD through phytosterol accumulation, oxidative stress, hepatic inflammatory pathways activation, and impaired bile flow. Created in BioRender. Abi-Aad, S. (2024). IFALD, intestinal failure-associated liver disease; PN, parenteral nutrition; SBS, short bowel syndrome.

Fig. 4

Proposed model of IFALD pathogenesis. (1) Intestinal dysfunction increases mucosal permeability, alters the intestinal barrier, and promotes dysbiosis and small bowel bacterial overgrowth. These changes disrupt the gut–liver axis, facilitating bacterial translocation and absorption of microbial-associated molecular patterns, such as lipopolysaccharides (LPSs), into the portal circulation. Recurrent CLABSI sepsis episodes further enhance LPS release and activation of innate immune pathways. (2) In the liver, LPSs interact with toll-like receptor-4 (TLR4) on hepatic macrophages, activating the inflammasome and an inflammatory cascade and cytokine release (including IL-1β, IL-6, and TNF-α). Binding to their receptors on the hepatocyte, through activation of NFκB signaling, these cytokines downregulate signaling and expression of hepatic nuclear receptors, including Farnesoid X receptor (FXR), liver X receptor (LXR), and liver receptor homolog 1 (LRH-1). (3) The inhibition of FXR, further exacerbated by toxic phytosterol accumulation from parenteral nutrition formulations, downregulates the canalicular bile acid transporter (BSEP) and the conjugated bilirubin transporter, multidrug resistance protein 2 (MRP2), promoting bile acid retention and cholestasis. On the other hand, the inhibition of LXR and LRH-1 downregulates canalicular ATP-binding cassette subfamily G member 5/8 ( ABCG5 , ABCG8 ), promoting hepatocyte accumulation of intravenously infused phytosterols. (4) Interruption of the enterohepatobiliary cycle following intestinal injury and resections reduces bile acid reabsorption by enterocytes, leading to diminished FXR activation in enterocytes, decreased fibroblast growth factor 19 (FGF19) production and secretion into the portal circulation, and reduced engagement of fibroblast growth factor receptor 4 (FGFR4) on hepatocytes. This disruption impairs the negative feedback regulating CYP7A1 , the rate-limiting enzyme in bile acid synthesis, allowing for continued synthesis and accumulation within hepatocytes of toxic bile acids that promote cholestatic liver injury. Created in BioRender. Abi-Aad, S. (2024). CLABSI, central line-associated bloodstream infection; CYP7A1 , cholesterol 7α-hydroxylase; IFALD, intestinal failure-associated liver disease; PN, parenteral nutrition; SBS, short bowel syndrome.