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.

Keywords

intestinal failure-associated liver disease - cholestasis - intestinal failure - lipid emulsions - parenteral nutrition-associated liver disease

Intestinal failure (IF) exists when the intestines are not able to process and absorb nutrients, electrolytes, and fluids to maintain adequate growth, development, and hydration. Parenteral nutrition (PN) is a lifesaving therapy for children and adults with IF. With the continuous improvement of PN formulations and their administration, it has become possible to deliver essential nutrients, including lipids, carbohydrates, proteins, vitamins, minerals, and micronutrients, for children and adults unable to tolerate enteral feedings.[1] Unfortunately, PN carries a significant risk of liver injury, known as intestinal failure-associated liver disease (IFALD), previously called PN-associated liver disease. This condition can range from cholestasis and inflammation to steatohepatitis and fibrosis, potentially leading to hepatocellular carcinoma. PN-associated cholestasis (PNAC) is often seen in children while steatohepatitis is more of a concern for adults on long-term PN; however, there is significant overlap.[2] IFALD was historically the leading indication for intestinal and multivisceral transplantation in children with IF. The evolving advances in the management of IFALD have led to new therapeutic and preventive approaches to improve patient outcomes and delay or avoid intestinal transplantation. This review will provide an update on the pathogenesis, treatment strategies, and challenges in treating infants and children with IFALD.

Epidemiological Aspects and Natural Progression of Intestinal Failure-Associated Liver Disease

IFALD remains a diagnostic challenge as there are no consensus criteria for its diagnosis, and incidence may vary depending on the varying definitions used in different studies.[3] The overall incidence of IFALD in patients receiving long-term PN is approximately 15 to 40% for adults and 40 to 60% for children, with infants, especially premature newborns with low birth weight, being at a greater risk.[4] The incidence of PNAC is related to the duration of PN; PNAC occurs in >60% of infants receiving PN for >2 months but <16% for PN duration <1 month.[5] In most studies, Phase 1 or active IFALD (characterized by cholestasis and inflammation) is defined as serum direct/conjugated bilirubin greater than 1.0 to 2.0 mg/dL and greater than 20% of total serum bilirubin (TB) in infants and children who have received PN for at least 14 days and in whom other causes of cholestasis have been excluded.[6] Phase 2 or chronic IFALD (characterized by hepatic steatosis and fibrosis) has no generally accepted diagnostic criteria; and because liver function tests do not always correlate with liver histology, liver biopsy, hepatic imaging, or elastography may be the only reliable tools to establish the diagnosis and assess the degree of liver injury.[3] A wide variety of changes may be visible on liver histology including cellular and canalicular cholestasis, portal bile duct plugs, variable portal inflammation, ductular reaction and prominent liver macrophages in Phase I/active IFALD ([Fig. 1]), and varying amounts of steatosis, hepatocyte swelling, and periportal fibrosis in Phase 2/chronic IFALD ([Fig. 2]).

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.

Currently, efforts are underway to discover noninvasive methods that accurately predict active IFALD. In a study of 77 children with IF who underwent liver biopsies, those with active IFALD had significantly higher levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transferase (GGT) and significantly lower levels of serum citrulline compared to those with chronic IFALD and those without IFALD. A GGT cut-off of 28 U/L, citrulline level of 18.5 μmol/L, and liver stiffness of 5.7 kPa (measured by vibration-controlled transient elastography) had sensitivities for detecting active IFALD of 86%, 83%, and 83%, and specificities of 85%, 71%, and 79%, respectively, with combinations providing higher accuracy.[7] Another biomarker being investigated as a surrogate for liver steatosis is fibroblast growth factor (FGF) 21 (FGF21), which is produced by the liver and regulates glucose and lipid metabolism. In a study of 35 pediatric patients with IF and PN dependence, serum FGF21 levels were significantly higher in those with liver steatosis compared to those without, and these levels correlated with the grade of steatosis.[8] These biomarker findings are promising; however, further studies are needed to assess the external validity of these tests.

In preterm infants without intestinal dysfunction, PNAC can often be reversed by advancing enteral feeding, with PN reduction or PN discontinuation.[5] In contrast, children with IF who remain chronically dependent on PN are more susceptible to IFALD and death.[9] The cholestatic/inflammatory IFALD phase is associated with the ongoing administration of PN, and the steatosis/fibrotic chronic phase may persist even after many years of PN discontinuation. In a study of 38 pediatric IF patients who underwent liver biopsies, Mutanen et al.[10] reported abnormal liver histology in 94% of patients on PN for an average of 74 months and in 77% of patients weaned off PN for an average of 8.8 years. There was significantly increased expression of liver α-smooth muscle actin, liver collagen I, and extracellular matrix adhesion molecules in both patients receiving PN and off PN compared to controls, indicating a persistent proinflammatory and fibrotic state even after weaning off PN; possibly because of ongoing intestinal homeostasis disruption observed in IF.[11] IFALD is a dynamic process evolving over months to years, and PN influences its resolution or progression. Mutanen et al.[7] showed in a study of 77 IF children who underwent liver biopsy at a mean age of 1.7 years, that 48% had acute IFALD, 21% had chronic IFALD, and 31% had no IFALD. After a median follow-up of 2.9 years, 48 patients had a repeat liver biopsy. Among those with initial acute IFALD (25 patients), 36% still had acute IFALD (with most remaining on PN), 29% progressed to chronic IFALD, and 29% regressed to no IFALD (most weaned off PN). Of those with initial chronic IFALD (8 patients), 12.5% had acute IFALD, 37.5% remained chronic (most still on PN), and 62.5% had no hepatotoxicity. Among those with no initial IFALD (14 patients), 21% developed acute or chronic IFALD while remaining on PN, and the rest did not.[7] In a multivariate analysis, Gattini et al.[12] demonstrated that IFALD reduces survival in pediatric IF in the contemporary era (hazard ratio (HR) =3.78, 95% CI 2.18–6.55). Consequently, early recognition and management of IFALD, along with addressing modifiable factors contributing to IFALD development, are essential.

Pathogenesis of Intestinal Failure-Associated Liver Disease

Patients with PN dependence are more susceptible to hepatic injury due to a combination of patient-related, infection-related, surgical-related, and PN-related factors ([Fig. 3]). The two phases of IFALD are each mediated by distinct pathophysiological mechanisms since the acute cholestatic/inflammatory phase resolves in the large majority of patients after discontinuation of PN while the chronic steatotic/fibrotic phase often persists long after PN is discontinued. In patients with IF and PN dependence, and in PNAC animal models, cholestasis is associated with the downregulation of canalicular bile acid and phytosterols export transporters, upregulation of the sinusoidal bile acid uptake transporter, and insufficient suppression of bile acid synthesis genes, whereas hepatic steatosis is associated with intestinal microbial dysbiosis, reactive oxygen species (ROS) accumulation, apoptosis, and increased FGF21 ([Fig. 4]). Although genetic factors may predispose infants to short bowel syndrome (SBS),[13] and hence the need for PN, we are not aware of clear associations of gene variants as risk factors for the development of IFALD, and this hypothesis has not been explored adequately.

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.[2] [14] 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.

Intravenous Lipid Emulsions and Intestinal Failure-Associated Liver Disease

PN therapies consist of a combination of fatty acids (FAs) from intravenous lipid emulsions (ILEs), amino acids, glucose, vitamins, electrolytes, and micronutrients, which may contribute to IFALD pathogenesis.[14] Factors like high carbohydrate and protein dose, excessive vitamin A, methionine, and manganese, photo-oxidation of vitamins, and deficiencies of taurine, choline, and glutamine, have been associated with the development of IFALD, however, none has been proven causative.[2]

ILEs are crucial for PN due to their high caloric density and delivery of essential FAs. The amount and source of ILEs are key in the pathogenesis of IFALD. Soybean oil-based lipid emulsion (SO-LE; such as Intralipid, Fresenius Kabi AG, Bad Homburg, Germany or Nutrilipid, B. Braun, Bethlehem, PA), a commonly used ILE, contains high levels of ω-6-polyunsaturated fatty acids (PUFAs), primarily linoleic acid (LA), a precursor of arachidonic acid (AA) which can be metabolized into proinflammatory eicosanoids, and a substrate for oxidative modification and lipid peroxidation.[15] In contrast, fish oil lipid emulsion (FO-LE), rich in ω-3 PUFAs, contains high amounts of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) with anti-inflammatory properties that can suppress cytokine release from macrophages, hepatocytes, and cholangiocytes.[16] SO-LE provides a significant source of energy and essential FA (LA and α-linolenic acid [ALA]) important for growth and neurodevelopment; however, its high concentration of phytosterols (see below), along with high ω-6:ω-3 ratio and low abundance of antioxidants, makes it more likely to induce IFALD.[17] In contrast, FO-LE with low phytosterols and high antioxidant α-tocopherol levels is less likely to cause liver injury and more likely to reverse cholestasis. In a study of patients with SBS and cholestasis, 44 patients who switched from 3 g/kg/day of SO-LE to the maximum recommended dose of 1 g/kg/day of FO-LE (Omegaven, Fresenius Kabi, Bad Homburg, Germany), experienced a sixfold faster reversal of cholestasis and reduced mortality compared to 49 historical controls who remained on SO-LE (3 g/kg/day).[18] Coconut oil is a source of medium-chain triglycerides (MCTs), which are rapidly metabolized by the liver. Due to their shorter chain and greater hydrophilicity, MCTs are absorbed enterally directly into the hepatic portal vein and undergo β-oxidation. In contrast, long-chain triglycerides (LCTs), like those found in SO-LE, when given enterally, enter the lymphatic system as chylomicrons, reach the systemic circulation, and are deposited in adipose and peripheral tissues.[19] Although some studies have demonstrated a reduction of FA accumulation with MCT use, a study of neonatal piglets who received PN with MCT/LCT-LE for 14 days showed significant increases in TB, direct bilirubin (DB), and AST, as well as inflammatory markers in the blood and ileal mucosa (IL-1B, TNF-α, NF-kβ) compared to neonatal piglets who received FO-LE. On the other hand, piglets who received FO-LE showed higher expression of antioxidant genes such as glutamate-cysteine ligase catalytic subunit, superoxide dismutase 1 (SOD1), and catalase compared to MCT/LCT emulsions.[20]

A newer combination of ILE (c-LE) composed of SO (30%), olive oil (25%), MCT (30%), and FO (15%) with added α-tocopherol (SMOF-Lipid™, Fresenius Kabi, Bad Homburg, Germany) is now approved for infants in many countries. Due to its favorable ω-6:ω-3 ratio and reduced phytosterol content, c-LE appears effective in reversing IFALD in most infants,[21] although its effect may be slower than that of FO-LE. In children under 18 years old, the administration of 1.6 g/kg of SMOF-Lipid resulted in a mean decrease of 67.7% in TB levels (p < 0.05) after 4 to 5 months and a significant increase in both height and weight compared to baseline.[22] Term and pre-term neonates with IF who received c-LE experienced a significant decrease in DB levels compared to those who received SO-LE; however, no significant differences were observed in growth parameters.[23] Additionally, a study of low-birth-weight infants (<1,500 g at birth) reported lower mean TB levels after 4 weeks of c-LE compared to SO-LE, reduced incidence of retinopathy of prematurity and intraventricular hemorrhage (complications that may be associated with essential FA deficiency) but no significant difference in z-score for weight, head circumference or crown–heel length.[24] c-LE, which can be given up to 3 g/kg/day in neonates and children <12 years and up to 2.5 g/kg/day for adolescents and adults, may be almost as effective as FO-LE in preventing IFALD with the benefit of providing the full lipid intake similar to SO-LE required for brain growth and development in infants.[25] [26]

Plant Sterols (Phytosterols)

Phytosterols play a key role in the development of IFALD.[27] Phytosterols are found in highest amounts in plant-based ILEs (e.g., SO-LE) and very low levels in non-plant-based ILEs (e.g., FO-LE), with c-LE in between.[2] The liver has limited ability to metabolize phytosterols as dietary phytosterols are usually minimally absorbed. In contrast, IV administration of phytosterols provides large loads requiring excretion via biliary sterol transporters ATP-binding cassette subfamily G member 5/8 (ABCG5/G8; sterolin) located on the canalicular membrane, or export into the intestinal lumen by intestinal epithelia.[28] Impaired biliary excretion, such as in cholestasis and downregulation of ABCG5/G8, results in markedly elevated hepatic and circulating concentrations of phytosterols. In several pediatric studies, exposure to phytosterols from PN formulations was indeed associated with cholestatic IFALD and elevated plasma and liver phytosterols' concentrations, including campesterol, stigmasterol, sitosterol, isofucosterol, sitostanol, and cholestane.[28] [29] A number of reports indicate that the phytosterols may themselves be causative of PNAC. In a mouse model preclinical study, the administration of a lab-generated low phytosterol SO-LE prevented biochemical and histologic liver injury compared to injury associated with standard SO-LE.[30] In another mouse model of PNAC and intestinal injury, substituting SO-LE with FO-LE prevented liver injury, but the addition of stigmasterol (a known cholestatic phytosterol) to FO-LE-induced liver injury, demonstrating the toxicity of phytosterols in the pathogenesis of IFALD. In addition, hepatic macrophage activation in PNAC is associated with the downregulation of canalicular ABCG5/G8 sterol transporters, further impairing biliary excretion of phytosterols. The mechanism by which elevated hepatic phytosterol levels cause cholestasis likely involves the interruption of Farnesoid X receptor (FXR) signaling and subsequent downregulation of the canalicular bile acid transporter, bile salt export pump (BSEP; ABCB11;[31] see below). Supporting this proposed mechanism, Mutanen et al.[32] reported that in children with IFALD, ratios of serum stigmasterol to cholesterol and avenasterol to cholesterol correlated with elevated serum bile acids and TB concentrations. These studies and others highlight the association of elevated concentrations of phytosterols with the development of cholestasis in infants and children with IFALD.

Farnesoid X Receptor

FXR, a nuclear hormone receptor encoded by NR1H4, regulates bile acid homeostasis by inducing a small heterodimer partner (SHP) or directly by interacting with promoter regions of genes involved in bile acid synthesis or transport.[33] Of importance related to PNAC and IFALD, infused phytosterols are taken up by hepatocytes and can directly interfere with hepatic FXR signaling, resulting in the downregulation of the canalicular bile acid transporter (BSEP) and the conjugated bilirubin transporter (multidrug resistance protein 2 encoded by the ABCC2 gene).[2] Phytosterols also activate hepatic macrophages, triggering proinflammatory cytokine release. These cytokines (including IL1-β) bind to receptors on hepatocytes, activating NF-kB signaling, which downregulates the expression of canalicular transporters of bile acids and phytosterols, impairing bile flow and resulting in elevated hepatic bile acid and phytosterol concentrations and cholestasis.[31] In a mouse model with intestinal injury, increased lipopolysaccharide (LPS) absorption combined with IV infusion of SO-LE led to hepatic macrophage activation, IL-1β and TNF-α production, and downregulation of hepatocyte mRNA expression of Nr1h4, Abcb11, and Abcc2, resulting in biochemical and histologic evidence of PNAC. The critical role of hepatic macrophages was demonstrated by the pharmacological blockage of the IL-1β receptor (by anakinra) or genetic deficiency of C-C motif chemokine receptor (CCR2), both of which prevented cholestasis.[34] The critical role of phytosterols was demonstrated in PN-fed mice, which did not develop PNAC when receiving FO-LE; however, when FO-LE was spiked with the phytosterol stigmasterol, hepatic macrophage activation, downregulation of canalicular transporters, and biochemical evidence of cholestasis were all observed.[31]

To further maintain bile homeostasis, hepatocyte FXR induces NR0B2/SHP, which binds to the cholesterol 7α-hydroxylase (CYP7A1) gene promoter to prevent the transcription of cholesterol 7α-hydroxylase, the rate-limiting enzyme of bile acid synthesis, thus preventing excessive bile acid accumulation in hepatocytes. In IFALD, this mechanism is dysregulated. In a study involving 33 pediatric patients with SBS and PN dependence,[35] hepatic mRNA expression of CYP7A1 was significantly elevated in both PN-dependent and weaned patients, compared to controls, suggesting persistent bile acid synthesis in the face of cholestasis, further worsening cholestatic injury. Similarly, other hepatocyte bile acid uptake transporters were upregulated in SBS and PNAC such as sodium taurocholate co-transporting polypeptide (NTCP/SLC10A1) for basolateral uptake of conjugated bile acids and organic anion-transporting polypeptide 1B1 (OATP1B1/SLCO1B1) for basolateral uptake of unconjugated bile acids, while export transporters like basolateral bile acid exporter multidrug resistance-associated protein 3 were downregulated. The combined effect was further promoting bile acid accumulation in hepatocytes.[35] This dysregulation of bile acid homeostasis may result in SBS patients, at least in part, from insufficient ileal secretion of FGF19, which normally downregulates CYP7A1 expression in the liver.[35]

Liver X Receptor

Liver X receptor (LXR) is a nuclear receptor encoded by Nr1h3 that regulates sterol metabolism through its binding to the promoter of ABCG5/8. These transporters are essential for canalicular export of infused phytosterols and are not upregulated appropriately in mouse models and children with PNAC. In an age-matched case–control study, infusion of PN in children with IF was associated with decreased expression of LXR, ABCG5, and ABCG8, as well as FXR and bile acid transporters,[36] which was related to hepatic inflammatory infiltrates, similar to the findings in the PNAC mouse model.

Liver Receptor Homolog 1

Liver receptor homolog 1 (LRH-1), encoded by Nr5a2, is another nuclear receptor that regulates sterol metabolism and bile acid synthesis. Ghosh et al.[33] found in a mouse PNAC model that LRH-1 activates the promoter region of ABCG5, ABCG8, and Cyp7A1 to maintain bile acid homeostasis. PN led to an NF-kB-dependent disruption of LRH-1 signaling that was associated with the downregulation of these bile transporters and PNAC. In a study in cultured hepatocytes, LRH-1 expression was decreased after exposure to phytosterols (stigmasterol + sitosterol) with or without the addition of LPS and with LPS alone, resulting in the downregulation of ABCG5/8 and stimulation of CYP7A1 and, subsequently, bile acid accumulation and PNAC. Furthermore, this process was mediated by IL-1 and NF-kβ signaling. An LRH-1 agonist, 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), prevented PNAC in this mouse model, suggesting this pathway as a possible therapeutic target.[37]

Ileal Fibroblast Growth Factor 19 Signaling and Intestinal Failure-Associated Liver Disease

FGF19, secreted by the ileum and upregulated in the human liver during cholestasis is an important negative feedback regulator of bile acid synthesis in humans. When bile acids secreted by the liver are reabsorbed in the intestine, they activate enterocyte FXR, which promotes the synthesis and release of FGF19 into the portal circulation. When FGF19 reaches the liver, it binds to FGF receptor 4 (FGFR4) on hepatocytes and inhibits CYP7A1, thus controlling bile acid synthesis. In patients with intestinal atresia, ileal resections, or significant ileal inflammation, many of whom require long-term PN, there may be insufficient intestinal synthesis and secretion of FGF19 and, thus, less negative feedback on bile acid synthesis. In a study of 52 patients with IF and PN dependence, circulating FGF19 levels were significantly lower compared to controls, particularly in those with total ileal and ileocecal valve resection and those with histological evidence of IFALD or portal inflammation.[38] Several factors may lead to lower FGF19 levels. Patients with IF may be unable to adequately reabsorb bile acids due to disruption in the enterohepatic circulation caused by mucosal inflammation or surgical removal of the distal small intestine, which expresses apical sodium-dependent bile acid transporters responsible for conjugated bile acid absorption.[35] The lower amount of bile acids reabsorbed into enterocytes would lead to insufficient stimulation of enterocyte FXR and inadequate FGF19 synthesis and secretion, impairing the negative feedback on hepatic bile acid synthesis. The overall result is excessive bile acid production during cholestasis and accumulation of potentially toxic bile acids in hepatocytes.[38] In this regard, Xiao et al.[39] recently reported that a serum FGF19 level below <107 pg/mL was a significant predictor of cholestasis and liver stiffness in patients with IF, with an OR of 13.184 (95% CI, 4.661–37.289, p < 0.001). Based on the effect of FGF19 on hepatic bile acid synthesis, FGF19 analogs have been explored as potential therapies to reduce hepatobiliary injury in other cholestatic diseases, but not in IFALD, to the best of our knowledge.[40]

Alterations of Intestinal Barrier Function

Intestinal barrier function may be impaired in IF through several mechanisms, including inflammation common in SBS, small intestine bacterial overgrowth (SIBO) and dysbiosis, portal hypertension, and immaturity. The resulting increased absorption of microbial-associated molecular patterns (MAMPs), such as LPS derived from the intestinal microbiota, likely plays an important role in hepatic macrophage recruitment and activation in IFALD.[2] Moreover, the intestine has an autoregeneration capacity mediated by intestinal stem cells (ISCs), which express the leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). To maintain gut integrity and intestinal repair, a high abundance of LGR5+ ISC is required. The renewal of these cells is dependent on mitochondrial FA oxidation, a process regulated by FXR. Using patient-derived organoid models obtained from intestinal biopsies of pediatric SBS with (n = 8) and without IFALD (n = 10), Zhao et al.[41] reported significant reductions of LGR5+ ISC population and impaired FXR signaling in those with IFALD. The addition of T-βMCA, an FXR antagonist, exacerbated enterocyte damage and downregulated FA oxidation gene expression. In contrast, the restoration of FXR function by an FXR agonist did not result in enterocyte proliferation or ISC recovery. These findings suggest that FXR may play a role in maintaining gut integrity through the regulation of FA oxidation; however, further studies are needed to understand how this may be affected in IFALD.

Microbiome Signature Changes

In patients with SBS, SIBO, small bowel dilation (>30 mm diameter), absence of the ileocecal valve, and altered gut permeability can lead to intestinal dysbiosis, increasing MAMPs and bacterial translocation.[2] Patients with IF experience significant gut microbiota changes, including reduced microbial diversity and overabundance of LPS-enriched bacteria like Bacilli (especially Lactobacilli) and Proteobacteria (especially Enterobacteriaceae), likely contributing to IFALD disease progression.[42] [43] When the gut barrier is disrupted, the liver is the first organ to receive intestinally derived MAMPs, toxins, and microorganisms.[44] For example, Proteobacteria expressing LPS can enter portal circulation if the intestinal mucosal barrier is compromised.[43] LPS can then bind to toll-like receptor 4 (TLR4) in hepatic macrophages, which signals downstream activation of proinflammatory cytokine expression and secretion and subsequent hepatocyte injury and cholestasis. In a mouse model with intestinal injury and total parenteral nutrition (TPN), genetically impaired TLR4 signaling abrogated the LPS-induced IL-6 expression in hepatic macrophages.[45] Moreover, mice treated with an antibiotic mixture that reduced intestinal bacteria by >97% did not show increased expression of hepatic proinflammatory cytokines (IL-6 and TNF-α) and experienced a significant reduction in liver injury.[45] In a preterm piglet model with TPN-induced IFALD, liver RNA sequencing revealed upregulated inflammatory pathways (NF-kβ, TNF-α, and TLRs), and cytokines compared to controls, while treatments with corticosteroids, anti-TNF antibody, NF-kβ inhibitor or cyclooxygenase-2 inhibitor downregulated these pathways, supporting that early IFALD is predominantly an inflammatory liver disease.[46] In addition, LPS-induction of TNF-α expression in mouse hepatocytes led to a decrease in mRNA expression of genes regulating bile acid and bilirubin export (Nr1h4/FXR, Abcb11, Abcc2), as well as reduced expression of sterol transporter pathway genes (Nr1h3/LXR, Abcg5, and Abcg8). Finally, knockout of TNF receptor in the PNAC mouse model or treatment with anti-TNF-antibody (infliximab) restored canalicular bile acid and sterol transporter expression and resulted in lower serum levels of bile acids, bilirubin, ALT, and AST.[47] Taken together, these studies indicate a key role for the gut microbiome and its products (and the gut–liver axis) in the pathogenesis of PNAC and IFALD.

Hepatic Steatosis and Novel Transcriptional Factors

Possibly one of the causes of hepatic steatosis in IFALD relates to the transcription factor HES6, which regulates FA metabolism and oxidation. Hes6 expression was significantly decreased in a mouse model of 7 days of TPN compared to control mice. Hes6 expression was found to be positively correlated with several taurine-conjugated bile acids but negatively correlated with hepatic triglycerides level (R = −0.68). Thus, HES6 may play a significant role in the development of hepatic steatosis during PN.[48]

Oxidative Stress and Apoptosis

Fas-mediated apoptosis has also been proposed as an important pathway leading to PNAC. In a mouse model of intestinal injury and 14 days of PN, Fas expression was induced in hepatocytes following IL-1β treatment and in hepatic mononuclear cells following LPS injection but was significantly decreased in IL-1β knockout mice, demonstrating the role of IL-1β signaling in Fas-mediated apoptosis. This rise in Fas expression was associated with elevated expression of caspase 8 and cleaved caspase 3 levels indicative of apoptosis. On the other hand, the IL-6-STAT pathway, which normally protects against liver damage, was also upregulated in the PNAC mouse model following IL-1β exposure, indicating a remaining protective effect in PNAC. The addition of GW4064 (an FXR agonist) further activated IL-6-STAT by binding to its promoter region, reducing expression of Fas, caspase 8, and cleaved caspase 3, thus providing a potential therapeutic target to overcome PNAC.[49] In addition, the downregulation of several NADH dehydrogenase subunits (mitochondrial complex I), particularly NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), has been associated with IFALD in both human and rat models. Disruption of mitochondrial oxidative phosphorylation in hepatocytes resulted in elevated ROS production and liver injury. Moreover, antioxidant treatment with MitoQ reduced ROS levels and significantly improved liver damage, cholestasis, and inflammation. Similarly, the restoration of NDUFS1 expression improved liver injury,[50] indicating potential pathways to explore that might alleviate liver injury.

Treatment and Prevention Strategies

The overall goal of managing patients with IF is to wean them from PN and establish complete enteral nutrition. However, there is a subset of children and infants with IF who cannot be tapered from PN and require care best delivered by a multidisciplinary team[1] that may employ strategies involving pharmacologic, nutritional, and surgical interventions to stabilize, reverse, and prevent liver injury.

Progression to Enteral Autonomy

Early advancement of enteral feedings, with the ultimate goal of full enteral feeding, if possible, will improve outcomes of patients with IF and IFALD.[51] Bolus enteral feedings may have an advantage over continuous tube feedings by stimulating intestinal motility, promoting mucosal hyperplasia and hypertrophy, reducing SIBO/dysbiosis, and increasing gallbladder contractility and bile flow, all of which may reduce the risk of cholestasis.[52] [53] However, a significant proportion of infants and children with IF cannot be weaned off PN[54] and only tolerate a limited amount of enteral nutrition and thus require additional approaches.

Lipid Emulsion Dose Reduction

Multiple studies show that reducing the total daily doses of ILEs may delay IFALD onset and reduce its severity.[55] [56] In neonates (≥36 weeks gestational age) with GI surgical disorders, administration of 1 g/kg/day of SO-LE for 6 months resulted in the same IFALD rate as 2 g/kg/day, but the weekly increase in DB was slower with the lower dose.[17] Another study in neonates ≥5 days old with GI disorders found no difference in cholestasis between low (1 g/kg/day) and traditional doses (3 g/kg/day) of SO-LE (30% vs. 38%, p = 0.7), but similarly showed a slower increase in DB with lower doses.[57] In contrast, others have shown that reducing the total amount of SO-LE to 1 g/kg/day can reverse cholestasis.[58] Postsurgical neonates receiving 1 g/kg/day of SO-LE had a 21% less incidence of IFALD compared to those receiving traditional SO-LE dose of 2 to 3 g/kg/day.[59] Cyclic PN and interruptions in delivery for several hours daily are recommended to decrease the risk for cholestasis, although this approach brings with it a risk of hypoglycemia, and there are limited data in children supporting a significant improvement in IFALD.[60] [61] However, in adult patients with IFALD, cyclic PN for an average of 12 days significantly improved AST, GGT, and TB, but no differences were observed in other liver tests.[60] Because neonates require appropriate nutritional and lipid intake to promote brain growth,[27] providing a suboptimal ILE dosage has the potential to lead to impaired brain growth or neurodevelopmental outcomes. In fact, a study in newborn piglets reported that a half dose of either SO-LE or FO-LE in TPN resulted in lower brain weight after 2 weeks compared to a full dose of either lipid emulsion.[62] Another study on neonatal piglets reported reduced brain weight with the use of low-dose FO-LE compared to a high dose of SO-LE.[62] However, to date, there have not been any studies showing impaired neurodevelopmental outcomes in human infants related to various doses and types of ILEs. Finally, there is concern that low-dose ILE therapy could increase the risk of essential FA deficiency, which could result in poor growth and increased risk of infection, thrombocytopenia, hepatitis, and hypertriglyceridemia.[63] However, this has not been observed in infants who have received 1 g/kg/day of ILE.[63]

Alternative Lipid Sources

The safety and efficacy of FO-LE in patients with IFALD led to the Food and Drug Administration (FDA) approval of Omegaven™ in 2018. Gura et al.[64] demonstrated that children with PN dependence and cholestasis who switched to 1 g/kg FO-LE had an adjusted HR of 6.8 (95% CI: 1.7–27.8) for reversing cholestasis, with lower rates of liver transplant and death compared to a historical matched cohort who did not receive FO-LE, and no adverse events, such as coagulopathy or essential FA deficiency, were reported. Another study demonstrated a 75% reversal of PNAC in cholestatic infants after 3 to 6 months of 1 g/kg/day FO-ILE compared to only 6% in those continuing SO-ILE at 2 to 3 g/kg/day.[65] Recent guidelines for pediatric and preterm PN have been published to guide clinicians with ILE use.[66] [67] FO-LE is not entirely without potential risk; high concentrations of ω-3 PUFAs (DHA and EPA) can increase bleeding risk due to competition with AA for cyclooxygenase, potentially reducing thromboxane A2 and impairing platelet aggregation. However, a comparative study found that the use of SO-LE in children with IFALD was associated with a higher bleeding risk than FO-LE, possibly due to the greater severity of liver dysfunction over time in those receiving SO-LE.[15] Because data are still lacking and FO-LE contains a low concentration of essential FAs and AA, it is currently not recommended for patients without IFALD.[63] Although FO-LE reverses cholestasis and liver inflammation (Phase 1 IFALD), hepatic fibrosis (Phase 2) may persist for years even after switching to FO-ILE,[68] suggesting that persistent hepatic fibrosis may be driven by intestinal dysfunction rather than PN administration in IFALD patients.

c-ILE (combined intravenous lipid emulsion; SMOFLipid™), another alternative, was FDA-approved for adults in 2016 and pediatric patients in 2022, including term and preterm neonates. Newer formulations of ILEs are emerging and showing promise in preclinical models; however, studies in adults and children are still needed to evaluate the efficacy and safety of these products. Vegaven™ (VV), a novel ILE, contains 30% of 18-carbon ω-3 FA, particularly ALA and stearidonic acid. In a mouse preclinical model, the administration of VV-TPN increased IL-10 and decreased IL-6 levels compared to standard LEs (SO-IL and Omegaven/FO-IL). VV also amplified the expression of LPS-binding protein, which detoxifies endotoxin in the liver, and upregulated the hepatic nuclear peroxisome proliferator-activated receptor α (PPARα), a transcription factor associated with FA oxidation and protection against steatohepatitis. The VV formula was shown to have greater resistance to oxidative modification compared to standard lipid emulsions.[69] Although these preclinical studies appear promising, it must be emphasized that VV has not been tested in infants and children and is not FDA-approved at this time, and thus requires further testing in humans to assess effectiveness and safety.

Pharmacotherapies

Choline is an essential nutrient involved in the formation of phosphatidylcholine, the major phospholipid transported into bile by canalicular MDR3. Previous studies have reported a decrease in plasma-free choline levels in older children and adult patients receiving long-term PN.[70] In a rat model, the addition of choline to PN improved liver function tests, decreased hepatic triglycerides levels, reduced ROS by 37%, and upregulated genes involved in FA oxidation, including hepatic PPARα and carnitine palmitoyl transferase I (CPT1).[71] These findings suggest that choline supplementation may protect against liver inflammation and steatosis, and clinical trials in humans are in progress. Another proposed intervention to help decrease oxidative stress and protect from liver injury is the administration of exogenous antioxidants in PN. Indeed, the generation of ROS and apoptosis are stimulated by the exposure of isolated rat hepatocytes to hydrophobic bile acids, and this can be reversed by a variety of antioxidants.[72] Moreover, mitochondrial dysfunction appears to be responsible for ROS generation and induction of cell death pathways in hepatocytes.[72] Supplementation with vitamin E prevented both mitochondrial dysfunction and ROS generation in rats given IV hydrophobic bile acids.[73] FO-LE and c-LE are supplemented with higher amounts of α-tocopherol than SO-LE to prevent peroxidation of the PUFAs within the emulsions, although it is not clear if the α-tocopherol is responsible for less cholestasis when these emulsions are administered compared to SO-LE. Supplementation of glutathione in guinea pigs with PN-dependence prevented hypermethylation and inactivation of detoxification genes and protected the liver against oxidative stress induced by lipid peroxidation.[74]

The administration of dexamethasone in preterm neonates before initiating PN may prevent the occurrence of PNAC. Among 78 preterm neonates receiving PN, the prior use of dexamethasone treatment for non-PNAC indications was significantly less common in those who developed PNAC compared to those who did not. Following a logistic regression, dexamethasone use was identified as a protective factor with an OR = −2.739 (p = 0.017).[75] Further studies are needed to examine the potential benefit of dexamethasone in preventing or treating PNAC in infants.

Medical Induction of Intestinal Adaptation

Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, can induce intestinal adaptation in patients with SBS and reduce the need for PN and intravenous volume support.[76] The efficacy of this therapy led to its FDA approval for children and adults with SBS and PN dependence. Additionally, a recent study in patients with SBS and PN dependence without preexisting liver diseases demonstrated significant mean changes from baseline values to 24 weeks for AST, ALT, and TB among those receiving teduglutide (n = 109) compared to controls (n = 59). However, no changes were observed in RIALP, GGT, platelets, Fibrosis-4 (FIB-4) score, and AST to Platelet Ratio Index (APRI).[77] An inhibitor of dipeptidyl peptidase-4 (DPP-4) (DPP4-I), an enzyme involved in glucose regulation and incretin degradation, is another therapy being investigated for use in patients with SBS; however, the results are still inconclusive. In a rat model of SBS with normal enteric feeding, DPP4-I administration significantly increased villous height in the jejunum and ileum, improved liver blood tests (lower AST, ALT levels), and reduced histological evidence of liver injury reflected in lower hepatic SAF (steatosis, activity, fibrosis) scores, compared to saline-infusion controls. However, no differences were noted for other liver markers.[78]

Emerging New Therapies

Newer targeted therapies have been proposed to potentially delay, reverse, or prevent PNAC and IFALD. FXR ligands (such as GW4064, obetacholic acid [OCA; FDA-approved for use in adults with primary biliary cholangitis], and others) are effective in reversing or preventing PNAC in mouse and piglet models. In a mouse model of intestinal injury and TPN, treatment with GW4064 resulted in a significant reduction in serum AST, ALT, bilirubin, and total serum bile acids and considerable restoration of FXR activity, along with the upregulation of its targets Abcb11, Abcc2, SHP, and ABCG 5/8 compared to controls.[79] Similarly, treatment with anti-TNF inhibitors (infliximab) or anti-IL-1β receptor therapy (anakinra) in the same mouse model significantly upregulated the expression of Abcb11, Abcc2, Abcg5/8, Nr1h3, and Nr1h4 and prevented cholestasis.[47] Recently, in a newborn piglet model receiving TPN, administration of OCA was shown to prevent PNAC.[80] These findings suggest that FXR analogs or TNF-α and IL-1β signaling inhibitors could serve as potential therapeutic options to reverse PNAC.

Microbiome Therapies

It is well-established now that SBS predisposes patients to small bowel dilation, favoring dysmotility, inflammation, intestinal dysbiosis, and SIBO, which promote barrier dysfunction and bacterial and MAMP translocation. These processes are likely involved in the pathogenesis of PNAC and IFALD.[81] Strategies to prevent or reverse IFALD are being tested and will leverage our knowledge of the gut–liver axis. Short-chain FAs, including acetate, propionate, and butyrate, provide energy for enterocytes and maintain gut integrity. Butyrate, produced by fermenting dietary carbohydrates by Ruminococcaceae or Lachnospiriaceae (depleted in the intestines of PN-dependent SBS patients), has been shown in preclinical studies to alleviate IFALD by maintaining the intestinal barrier and reducing bacterial translocation to the liver.[44] Other approaches are directed at modifying the gut microbiota through antibiotics, prebiotics, probiotics, or synbiotics. Probiotics, such as lactobacillus plantarum (L. plantarum) and Lactobacillus johnsonii (L. johnsonii), were shown to prevent IFALD in preclinical studies. In newborn piglets receiving PN, those who received PN + L. plantarum versus PN controls had better intestinal integrity with increased tight junction protein expression (TPJ1, CDH1, CLDN1), higher expression of intestinal FGF 19 and SHP, and lower hepatic CYP7A1 expression associated with reduced hepatic steatosis and lobular inflammation.[82] Similarly, rats treated with PN + L. johnsonii had lower levels of the bile acid glycochenodeoxycholic acid, a known inducer of apoptosis, and showed less hepatocyte apoptosis compared to rats fed with TPN only. However, the administration of L. johnsonii did not reduce the hepatic expression of CYP7A1. There are no reports to date of improved hepatic outcomes using these various modalities to modify the gut microbiome in infants or children with IFALD or PNAC. Importantly, the safety of these pre- and probiotics in humans, particularly children, with IFALD remains unknown, thus, further studies in humans will be required to assess the potential efficacy and safety of pre- and probiotics in IFALD.[83]

Prevention of Central Line-Associated Bloodstream Infections

Recurrent central line-associated bloodstream infections (CLABSIs) are linked to higher risks for the development of IFALD; therefore, implementing preventive strategies is crucial for reducing the incidence and severity of IFALD.[1] [84] [85] CLABSIs are likely involved in IFALD through the release of LPS and other MAMPs into the systemic circulation from gram-negative infections, which can activate macrophages and other inflammatory cells when they reach the liver, inducing downregulation of hepatocyte bile and sterol transporters, leading to cholestasis.[45] The use of ethanol locks or antimicrobial taurolidine–citrate locks and meticulous care of central venous catheters have been shown to reduce the incidence of CLABSIs and are employed by most multidisciplinary IF care teams.[86] [87]

Surgical Lengthening Procedures

Surgical lengthening and tapering procedures and restoration of intestinal continuity with the closure of intestinal stroma, especially at an early age (<1 year), can improve enterohepatic circulation and restore intestinal motility, which may reduce dysbiosis. Importantly, these procedures may increase the surface area of intestinal mucosa, leading to faster advancement of enteral feedings and attainment of enteral autonomy. Although these approaches are important in managing infants and children with SBS, trials have not demonstrated the direct benefits of non-transplant surgery in the management and prevention of IFALD.[2]

Organ Transplantation

The need for small bowel or multivisceral transplantation in managing IF and SBS has decreased in the United States over the past two decades. This is due to advancements in multidisciplinary care, including optimized nutrition, improved ILE, prevention of CLABSIs, use of GLP-2 agonists, and intestinal lengthening procedures.[88] Organ transplantation is usually reserved for severe IFALD cases unresponsive to other interventions and associated with end-stage liver disease. The organ transplantation options include isolated small bowel transplantation for patients with severe IF complications or loss of IV access but with minimal or no signs of IFALD, isolated liver transplantation for portal hypertension and cirrhosis but with adequate intestinal adaptation, and combined liver–intestine transplants (or multivisceral transplants) for patients with complete intestinal aganglionosis, intestinal pseudo-obstruction, or severe portal hypertension.[89] However, the outcome and prognosis of IF patients requiring organ transplantation are not optimal. The Pediatric IF Consortium reported on 272 infants with IF and observed an incidence of enteral autonomy of 47%, death of 27%, and intestinal transplantation of 26%.[90] More recently, Norsa et al.[91] reported that an estimated 5-year survival rate for pediatric patients with neonatal very SBS was 68%, with survival following intestinal transplant of 60% compared to a 100% survival rate for those who remained on long-term PN without life-threatening complications. Despite strong international efforts, outcomes following intestinal transplants fall short of those for other solid organ transplants, mandating doubling down on efforts for continued improvements in medical, nutritional, and surgical management of IF.

Conclusion

IFALD, including PNAC and steatohepatitis, is a life-threatening complication of long-term TPN. The pathogenesis of IFALD is complex, but ongoing research is clarifying the role of the gut–liver axis and innate immunity, IV lipid emulsions, dysregulation of bile acid metabolism, and intestinal dysbiosis. Innovative medical therapies are emerging, and the need for organ transplants is declining. However, PN dependence and liver injury remain a challenge, especially for patients with IF unable to be weaned off PN and receive enteral nutrition.

Concluding Remarks

There is a need to establish consensus criteria for diagnosis and categorization of the two phases of IFALD (cholestatic/inflammatory and steatotic/fibrotic), and search for noninvasive diagnostic tools or biomarkers to evaluate IFALD in infants and children with IF. The identification of effective preventative and therapeutic strategies is a high priority. Finally, future research should also focus on novel therapeutics to enhance intestinal adaptation to allow for advancing enteral feedings and reduction of the need for PN in people with SBS.

Conflict of Interest

None declared.

• References

• 1 Wichman BE, Nilson J, Govindan S. et al. Beyond lipids: Novel mechanisms for parenteral nutrition-associated liver disease. Nutr Clin Pract 2022; 37 (02) 265-273
• 2 Khalaf RT, Sokol RJ. New insights into intestinal failure-associated liver disease in children. Hepatology 2020; 71 (04) 1486-1498
• 3 Tabone T, Mooney P, Donnellan C. Intestinal failure-associated liver disease: Current challenges in screening, diagnosis, and parenteral nutrition considerations. Nutr Clin Pract 2024; 39 (05) 1003-1025
• 4 Zafirovska M, Zafirovski A, Rotovnik Kozjek N. Current insights regarding intestinal failure-associated liver disease (IFALD): A narrative review. Nutrients 2023; 15 (14) 15
• 5 Lauriti G, Zani A, Aufieri R. et al. Incidence, prevention, and treatment of parenteral nutrition-associated cholestasis and intestinal failure-associated liver disease in infants and children: a systematic review. JPEN J Parenter Enteral Nutr 2014; 38 (01) 70-85
• 6 Lal S, Pironi L, Wanten G. et al.; Home Artificial Nutrition & Chronic Intestinal Failure Special Interest Group of the European Society for Clinical Nutrition and Metabolism (ESPEN). Clinical approach to the management of Intestinal Failure Associated Liver Disease (IFALD) in adults: A position paper from the Home Artificial Nutrition and Chronic Intestinal Failure Special Interest Group of ESPEN. Clin Nutr 2018; 37 (6 Pt A): 1794-1797
• 7 Mutanen A, Lohi J, Merras-Salmio L, Koivusalo A, Pakarinen MP. Prediction, identification and progression of histopathological liver disease activity in children with intestinal failure. J Hepatol 2021; 74 (03) 593-602
• 8 Mutanen A, Heikkilä P, Lohi J, Raivio T, Jalanko H, Pakarinen MP. Serum FGF21 increases with hepatic fat accumulation in pediatric onset intestinal failure. J Hepatol 2014; 60 (01) 183-190
• 9 Spencer AU, Neaga A, West B. et al. Pediatric short bowel syndrome: redefining predictors of success. Ann Surg 2005; 242 (03) 403-409 , discussion 409–412
• 10 Mutanen A, Lohi J, Heikkilä P, Koivusalo AI, Rintala RJ, Pakarinen MP. Persistent abnormal liver fibrosis after weaning off parenteral nutrition in pediatric intestinal failure. Hepatology 2013; 58 (02) 729-738
• 11 Mutanen A, Lohi J, Sorsa T, Jalanko H, Pakarinen MP. Features of liver tissue remodeling in intestinal failure during and after weaning off parenteral nutrition. Surgery 2016; 160 (03) 632-642
• 12 Gattini D, Roberts AJ, Wales PW. et al. Trends in pediatric intestinal failure: a multicenter, multinational study. J Pediatr 2021; 237: 16-23.e4
• 13 Wang Y, Chen S, Yan W. et al. Congenital short-bowel syndrome: clinical and genetic presentation in China. JPEN J Parenter Enteral Nutr 2021; 45 (05) 1009-1015
• 14 Rangel SJ, Calkins CM, Cowles RA. et al.; 2011 American Pediatric Surgical Association Outcomes and Clinical Trials Committee. Parenteral nutrition-associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J Pediatr Surg 2012; 47 (01) 225-240
• 15 Gura KM, Calkins KL, Premkumar MH, Puder M. Use of intravenous soybean and fish oil emulsions in pediatric intestinal failure-associated liver disease: A multicenter integrated analysis report on extrahepatic adverse events. J Pediatr 2022; 241: 173-180.e1
• 16 Hao W, Wong OY, Liu X, Lee P, Chen Y, Wong KK. ω-3 fatty acids suppress inflammatory cytokine production by macrophages and hepatocytes. J Pediatr Surg 2010; 45 (12) 2412-2418
• 17 Gupta K, Wang H, Amin SB. Soybean-oil lipid minimization for prevention of intestinal failure-associated liver disease in late-preterm and term infants with gastrointestinal surgical disorders. JPEN J Parenter Enteral Nutr 2021; 45 (06) 1239-1248
• 18 Puder M, Valim C, Meisel JA. et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg 2009; 250 (03) 395-402
• 19 Lee Y-Y, Tang T-K, Chan E-S. et al. Medium chain triglyceride and medium-and long chain triglyceride: metabolism, production, health impacts and its applications - a review. Crit Rev Food Sci Nutr 2022; 62 (15) 4169-4185
• 20 Chen S, Xiao Y, Liu Y. et al. Fish oil-based lipid emulsion alleviates parenteral nutrition-associated liver diseases and intestinal injury in piglets. JPEN J Parenter Enteral Nutr 2022; 46 (03) 709-720
• 21 Diamond IR, Grant RC, Pencharz PB. et al. Preventing the progression of intestinal failure-associated liver disease in infants using a composite lipid emulsion: a pilot randomized controlled trial of SMOFlipid. JPEN J Parenter Enteral Nutr 2017; 41 (05) 866-877
• 22 Wassef J, Lipkin E, Hardigan P, Duro D. Trends in liver profile and nutrition outcomes in children undergoing intestinal rehabilitation using a mixed lipid injectable emulsion. Nutr Clin Pract 2022; 37 (05) 1180-1189
• 23 Hudson AS, Tyminski N, Turner JM, Silverman JA. Intestinal failure-associated liver disease and growth pre- and post-transition to a composite lipid emulsion. J Pediatr Gastroenterol Nutr 2023; 76 (06) 830-836
• 24 Hill NS, Cormack BE, Little BS, Bloomfield FH. Growth and clinical outcome in very low-birth-weight infants after the introduction of a multicomponent intravenous lipid emulsion. JPEN J Parenter Enteral Nutr 2020; 44 (07) 1318-1327
• 25 Yildizdas HY, Poyraz B, Atli G. et al. Effects of two different lipid emulsions on antioxidant status, lipid peroxidation and parenteral nutrition-related cholestasis in premature babies, a randomized-controlled study. Pediatr Neonatol 2019; 60 (04) 359-367
• 26 Gallini F, Pelosi MS, De Rose DU. et al. Neurodevelopmental outcomes in preterm infants receiving a multicomponent vs. a soybean-based lipid emulsion: 24 month follow-up of a randomized controlled trial. Nutrients 2022; 15 (01) 58
• 27 Nandivada P, Fell GL, Gura KM, Puder M. Lipid emulsions in the treatment and prevention of parenteral nutrition-associated liver disease in infants and children. Am J Clin Nutr 2016; 103 (02) 629S-634S
• 28 Clayton PT, Bowron A, Mills KA, Massoud A, Casteels M, Milla PJ. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology 1993; 105 (06) 1806-1813
• 29 Hukkinen M, Mutanen A, Nissinen M, Merras-Salmio L, Gylling H, Pakarinen MP. Parenteral plant sterols accumulate in the liver reflecting their increased serum levels and portal inflammation in children with intestinal failure. JPEN J Parenter Enteral Nutr 2017; 41 (06) 1014-1022
• 30 Fligor SC, Hirsch TI, Tsikis ST. et al. Intestinal failure-associated liver disease model: a reduced phytosterol intravenous lipid emulsion prevents liver injury. Pediatr Res 2024
• 31 El Kasmi KC, Anderson AL, Devereaux MW. et al. Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease. Sci Transl Med 2013; 5 (206) 206ra137
• 32 Mutanen A, Nissinen MJ, Lohi J, Heikkilä P, Gylling H, Pakarinen MP. Serum plant sterols, cholestanol, and cholesterol precursors associate with histological liver injury in pediatric onset intestinal failure. Am J Clin Nutr 2014; 100 (04) 1085-1094
• 33 Ghosh S, Devereaux MW, Anderson AL. et al. NF-κB regulation of LRH-1 and ABCG5/8 potentiates phytosterol role in the pathogenesis of parenteral nutrition-associated cholestasis. Hepatology 2021; 74 (06) 3284-3300
• 34 El Kasmi KC, Vue PM, Anderson AL. et al. Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis. Nat Commun 2018; 9 (01) 1393
• 35 Mutanen A, Pakarinen MP. Featuring molecular regulation of bile acid homeostasis in pediatric short bowel syndrome. Clin Res Hepatol Gastroenterol 2023; 47 (09) 102220
• 36 Mutanen A, Lohi J, Heikkilä P, Jalanko H, Pakarinen MP. Liver inflammation relates to decreased canalicular bile transporter expression in pediatric onset intestinal failure. Ann Surg 2018; 268 (02) 332-339
• 37 Ghosh S, Devereaux MW, Liu C, Sokol RJ. LRH-1 agonist DLPC through STAT6 promotes macrophage polarization and prevents parenteral nutrition-associated cholestasis in mice. Hepatology 2024; 79 (05) 986-1004
• 38 Mutanen A, Lohi J, Heikkilä P, Jalanko H, Pakarinen MP. Loss of ileum decreases serum fibroblast growth factor 19 in relation to liver inflammation and fibrosis in pediatric onset intestinal failure. J Hepatol 2015; 62 (06) 1391-1397
• 39 Xiao Y, Maitiabula G, Wang H. et al. Predictive value of serum fibroblast growth factor 19 and liver stiffness for intestinal failure associated liver disease-cholestasis. Clin Nutr ESPEN 2024; 59: 89-95
• 40 Li X, Lu W, Kharitonenkov A, Luo Y. Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases. J Intern Med 2024; 295 (03) 292-312
• 41 Zhao Y, Wang Y, Jiang L, Cai W, Yan J. Impaired intestinal FXR signaling is involved in aberrant stem cell function leading to intestinal failure-associated liver disease in pediatric patients with short bowel syndrome. FASEB J 2024; 38 (15) e23847
• 42 Korpela K, Mutanen A, Salonen A, Savilahti E, de Vos WM, Pakarinen MP. Intestinal microbiota signatures associated with histological liver steatosis in pediatric-onset intestinal failure. JPEN J Parenter Enteral Nutr 2017; 41 (02) 238-248
• 43 Ralls MW, Miyasaka E, Teitelbaum DH. Intestinal microbial diversity and perioperative complications. JPEN J Parenter Enteral Nutr 2014; 38 (03) 392-399
• 44 Jiang L, Wang Y, Xiao Y. et al. Role of the gut microbiota in parenteral nutrition-associated liver disease: from current knowledge to future opportunities. J Nutr 2022; 152 (02) 377-385
• 45 El Kasmi KC, Anderson AL, Devereaux MW. et al. Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. Hepatology 2012; 55 (05) 1518-1528
• 46 Fligor SC, Tsikis ST, Hirsch TI. et al. Inflammation drives pathogenesis of early intestinal failure-associated liver disease. Sci Rep 2024; 14 (01) 4240
• 47 El Kasmi KC, Anderson AL, Devereaux MW. et al. Interrupting tumor necrosis factor-alpha signaling prevents parenteral nutrition-associated cholestasis in mice. JPEN J Parenter Enteral Nutr 2022; 46 (05) 1096-1106
• 48 Jiang L, Wang N, Cheng S. et al. RNA-sequencing identifies novel transcriptomic signatures in intestinal failure-associated liver disease. J Pediatr Surg 2022; 57 (09) 158-165
• 49 Ghosh S, Devereaux MW, Anderson AL, El Kasmi KC, Sokol RJ. Stat3 role in the protective effect of FXR Agonist in parenteral nutrition-associated cholestasis. Hepatol Commun 2023; 7 (03) e0056
• 50 Wan S, Maitiabula G, Wang P. et al. Down regulation of NDUFS1 is involved in the progression of parenteral-nutrition-associated liver disease by increasing oxidative stress. J Nutr Biochem 2023; 112: 109221
• 51 Shores DR, Alaish SM, Aucott SW. et al. Postoperative enteral nutrition guidelines reduce the risk of intestinal failure-associated liver disease in surgical infants. J Pediatr 2018; 195: 140-147.e1
• 52 Sharman-Koendjbiharie M, Piena-Spoel M, Hopman WP, Albers MJ, Jansen JB, Tibboel D. Gastrointestinal hormone secretion after surgery in neonates with congenital intestinal anomalies during starvation and introduction of enteral nutrition. J Pediatr Surg 2003; 38 (11) 1602-1606
• 53 Dodge ME, Bertolo RF, Brunton JA. Enteral feeding induces early intestinal adaptation in a parenterally fed neonatal piglet model of short bowel syndrome. JPEN J Parenter Enteral Nutr 2012; 36 (02) 205-212
• 54 Pironi L, Arends J, Bozzetti F. et al.; Home Artificial Nutrition & Chronic Intestinal Failure Special Interest Group of ESPEN. ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr 2016; 35 (02) 247-307
• 55 Nehra D, Fallon EM, Carlson SJ. et al. Provision of a soy-based intravenous lipid emulsion at 1 g/kg/d does not prevent cholestasis in neonates. JPEN J Parenter Enteral Nutr 2013; 37 (04) 498-505
• 56 Levit OL, Calkins KL, Gibson LC. et al. Low-dose intravenous soybean oil emulsion for prevention of cholestasis in preterm neonates. JPEN J Parenter Enteral Nutr 2016; 40 (03) 374-382
• 57 Calkins KL, Havranek T, Kelley-Quon LI. et al. Low-dose parenteral soybean oil for the prevention of parenteral nutrition-associated liver disease in neonates with gastrointestinal disorders. JPEN J Parenter Enteral Nutr 2017; 41 (03) 404-411
• 58 Rollins MD, Ward RM, Jackson WD. et al. Effect of decreased parenteral soybean lipid emulsion on hepatic function in infants at risk for parenteral nutrition-associated liver disease: a pilot study. J Pediatr Surg 2013; 48 (06) 1348-1356
• 59 Sanchez SE, Braun LP, Mercer LD, Sherrill M, Stevens J, Javid PJ. The effect of lipid restriction on the prevention of parenteral nutrition-associated cholestasis in surgical infants. J Pediatr Surg 2013; 48 (03) 573-578
• 60 Arenas Villafranca JJ, Nieto Guindo M, Álvaro Sanz E, Moreno Santamaria M, Garrido Siles M, Abilés J. Effects of cyclic parenteral nutrition on parenteral-associated liver dysfunction parameters. Nutr J 2017; 16 (01) 66
• 61 Bae HJ, Shin SH, Kim EK, Kim HS, Cho YS, Gwak HS. Effects of cyclic parenteral nutrition on parenteral nutrition-associated cholestasis in newborns. Asia Pac J Clin Nutr 2019; 28 (01) 42-48
• 62 Josephson J, Turner JM, Field CJ. et al. parenteral soy oil and fish oil emulsions: impact of dose restriction on bile flow and brain size of parenteral nutrition-fed neonatal piglets. JPEN J Parenter Enteral Nutr 2015; 39 (06) 677-687
• 63 Chan AP, Rostas S, Rogers S, Martin CR, Calkins KL. Parenteral nutrition in the neonatal intensive care unit: intravenous lipid emulsions. Clin Perinatol 2023; 50 (03) 575-589
• 64 Gura KM, Lee S, Valim C. et al. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics 2008; 121 (03) e678-e686
• 65 Calkins KL, Dunn JC, Shew SB. et al. Pediatric intestinal failure-associated liver disease is reversed with 6 months of intravenous fish oil. JPEN J Parenter Enteral Nutr 2014; 38 (06) 682-692
• 66 Lapillonne A, Fidler Mis N, Goulet O, van den Akker CHP, Wu J, Koletzko B. ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric parenteral nutrition. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Lipids. Clin Nutr 2018; 37 (6 Pt B): 2324-2336
• 67 Robinson DT, Calkins KL, Chen Y. et al. Guidelines for parenteral nutrition in preterm infants: The American Society for Parenteral and Enteral Nutrition. JPEN J Parenter Enteral Nutr 2023; 47 (07) 830-858
• 68 Mercer DF, Hobson BD, Fischer RT. et al. Hepatic fibrosis persists and progresses despite biochemical improvement in children treated with intravenous fish oil emulsion. J Pediatr Gastroenterol Nutr 2013; 56 (04) 364-369
• 69 Lucchinetti E, Lou PH, Holtzhauer G. et al. Novel lipid emulsion for total parenteral nutrition based on 18-carbon n-3 fatty acids elicits a superior immunometabolic phenotype in a murine model compared with standard lipid emulsions. Am J Clin Nutr 2022; 116 (06) 1805-1819
• 70 Bernhard W, Böckmann KA, Minarski M. et al. Evidence and perspectives for choline supplementation during parenteral nutrition-a narrative review. Nutrients 2024; 16 (12) 16
• 71 Zhu J, Lu T, Chen F. et al. Choline protects against intestinal failure-associated liver disease in parenteral nutrition-fed immature rats. JPEN J Parenter Enteral Nutr 2018; 42 (02) 436-445
• 72 Sokol RJ, Dahl R, Devereaux MW, Yerushalmi B, Kobak GE, Gumpricht E. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J Pediatr Gastroenterol Nutr 2005; 41 (02) 235-243
• 73 Sokol RJ, McKim Jr JM, Goff MC. et al. Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat. Gastroenterology 1998; 114 (01) 164-174
• 74 Mungala Lengo A, Mohamed I, Lavoie JC. Glutathione supplementation prevents neonatal parenteral nutrition-induced short- and long-term epigenetic and transcriptional disruptions of hepatic H₂O₂ metabolism in guinea pigs. Nutrients 2024; 16 (06) 16
• 75 Jiang S, Hu Q, Zhang J. Dexamethasone may affect the occurrence of parenteral nutrition-associated cholestasis in preterm neonates. Front Pediatr 2022; 10: 1023798
• 76 El Khatib M, Billiauws L, Joly F. The indications and results of the use of teduglutide in patients with short bowel. Curr Opin Clin Nutr Metab Care 2023; 26 (05) 449-454
• 77 Micic D, Robinson I, Kidd T, Terreri B, Raphael BP. Teduglutide improves liver chemistries in short bowel syndrome-associated intestinal failure: Post hoc analysis. Nutr Clin Pract 2024; 39 (03) 634-640
• 78 Sueyoshi R, Furuhashi N, Ishii J. et al. Decreased liver damage in rat models of short bowel syndrome through DPP4 inhibition. Pediatr Surg Int 2022; 39 (01) 21
• 79 El Kasmi KC, Ghosh S, Anderson AL. et al. Pharmacologic activation of hepatic farnesoid X receptor prevents parenteral nutrition-associated cholestasis in -mice. Hepatology 2022; 75 (02) 252-265
• 80 Jiang Y, Fang Z, Guthrie G. et al. Selective agonism of liver and gut FXR prevents cholestasis and intestinal atrophy in parenterally fed neonatal pigs. biioRxiv [Preprint]; 2024. Sep 7: 2024.09.03.611073. Accessed March 9, 2025
• 81 Hukkinen M, Mutanen A, Pakarinen MP. Small bowel dilation in children with short bowel syndrome is associated with mucosal damage, bowel-derived bloodstream infections, and hepatic injury. Surgery 2017; 162 (03) 670-679
• 82 Wang W, Wang Y, Liu Y. et al. Lactobacillus plantarum supplementation alleviates liver and intestinal injury in parenteral nutrition-fed piglets. JPEN J Parenter Enteral Nutr 2022; 46 (08) 1932-1943
• 83 Xu J, Zhou Y, Cheng S. et al. Lactobacillus johnsonii attenuates liver steatosis and bile acid dysregulation in parenteral nutrition-fed rats. Metabolites 2023; 13 (10) 13
• 84 Beath SV, Davies P, Papadopoulou A. et al. Parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk factors. J Pediatr Surg 1996; 31 (04) 604-606
• 85 Hermans D, Talbotec C, Lacaille F, Goulet O, Ricour C, Colomb V. Early central catheter infections may contribute to hepatic fibrosis in children receiving long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 2007; 44 (04) 459-463
• 86 Lambe C, Poisson C, Talbotec C, Goulet O. Strategies to reduce catheter-related bloodstream infections in pediatric patients receiving home parenteral nutrition: the efficacy of taurolidine-citrate prophylactic-locking. JPEN J Parenter Enteral Nutr 2018; 42 (06) 1017-1025
• 87 Oliveira C, Nasr A, Brindle M, Wales PW. Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. Pediatrics 2012; 129 (02) 318-329
• 88 Smith JM, Weaver T, Skeans MA. et al. OPTN/SRTR 2017 Annual Data Report: Intestine. Am J Transplant 2019; 19 (Suppl. 02) 284-322
• 89 Kaufman SS, Atkinson JB, Bianchi A. et al.; American Society of Transplantation. Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation. Pediatr Transplant 2001; 5 (02) 80-87
• 90 Squires RH, Duggan C, Teitelbaum DH. et al.; Pediatric Intestinal Failure Consortium. Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. J Pediatr 2012; 161 (04) 723-8.e2
• 91 Norsa L, Artru S, Lambe C. et al. Long term outcomes of intestinal rehabilitation in children with neonatal very short bowel syndrome: Parenteral nutrition or intestinal transplantation. Clin Nutr 2019; 38 (02) 926-933

Publication History

Received: 14 December 2024

Accepted: 14 February 2025

Accepted Manuscript online:
27 February 2025

Article published online:
18 March 2025