Treatment Of Intestinal Failure-associated Liver Disease Research Articles

A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure–Associated Liver Disease in Preterm Yorkshire Piglets

At least 20 to 30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD. Preterm Yorkshire piglets were delivered by caesarean section and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium chain triglycerides (MCT) vehicle control or SEFA-6179. Compared to MCT vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs. <0.2 mg/dL, P=0.01; total bilirubin: 2.7 vs. 0.4 mg/dL, P=0.02; gamma glutamyl transferase 172 vs. 30 U/L, P=0.01). SEFA-6179 also prevented steatosis (45.6 vs. 13.9 mg triglycerides/g liver tissue, P=0.009), reduced bile duct proliferation (1.6 vs. 0.5% area cytokeratin 7 positive, P=0.009), and reduced fibrosis assessed by a masked pathologist (median Ishak score 3 vs. 1, P=0.007). RNA-Seq of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its in vitro receptor activity (GPR84/PPARα/PPARγ agonist). In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis, and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial.

IFALD in children: What's new? A narrative review.

Intestinal failure-associated liver disease (IFALD) is a progressive liver disease complicating intestinal failure (IF). It is a preventable and reversible condition, but at the same time, a potential cause of liver cirrhosis and an indication to combined or non-combined liver and small bowel transplantation. The diagnostic criteria are not yet standardized, so that its prevalence varies widely in the literature. Pathophysiology seems to be multifactorial, related to different aspects of intestinal failure and not only to the long-term parenteral nutrition treatment. The survival rates of children with IF have increased, so that the main problems today are preventing complications and ensuring a good quality of life. IFALD is one of the most important factors that limit long-term survival of patients with IF. For this reason, more and more interest is developing around it and the number of published articles is increasing rapidly. The purpose of this narrative review was to focus on the main aspects of the etiology, pathophysiology, management, prevention, and treatment of IFALD, based on what has been published mainly in the last 10 years. Controversies and current research gaps will be highlighted with the aim to pave the way for new project and high-quality clinical trials.

Lipid Emulsion Use in Pediatric Patients Requiring Long-Term Parenteral Nutrition.

The ability to deliver nutrients via parenteral nutrition (PN) has markedly improved the prognosis of infants and children with intestinal failure. Technical refinements and advances in knowledge have led to the development of highly sophisticated PN solutions that are tailored to meet the needs of pediatric patients. However, children who require long-term PN have an increased risk of complications such as catheter-related sepsis, liver disease, and bone disease. Although the pathogenesis of intestinal failure associated liver disease (IFALD) is multifactorial, studies have identified a possible link between the dose of lipid emulsions based on soybean oil and cholestasis, shown to occur with a significantly higher frequency in patients receiving >1 g lipids/kg/d. Potential contributing factors include oxidative stress, high ω-6 polyunsaturated fatty acid (PUFA) and phytosterol content, and relatively low α-tocopherol levels. Lipid emulsions containing fish oil offer potential advantages compared with traditional emulsions with a high soybean oil content, such as decreased ω-6 and increased ω-3 PUFA concentrations, high concentrations of α-tocopherol, and reduced phytosterol content. Studies in PN-dependent children at risk for IFALD have shown that lipid emulsions containing fish oil reduce the risk of cholestasis and improve biochemical measures of hepatobiliary function compared with pure soybean oil emulsions. This review summarizes evidence regarding the role of lipid emulsions in the management of pediatric patients with intestinal failure requiring long-term PN, with a particular focus on the prevention and treatment of IFALD.

Use of Lipids in Adult Patients Requiring Parenteral Nutrition in the Home Setting.

It is estimated that over 25,000 Americans receive home parenteral nutrition (HPN), mostly because of intestinal failure (IF). Although there is significant variability in the fluid and energy needs of patients receiving HPN, intravenous lipid emulsions (ILEs) are an essential part of the macronutrient composition, serving as an excellent source of non-protein energy, as well as supplying essential fatty acids. However, the long-term use of ILEs in particular may be associated with some detrimental health effects, such as intestinal failure associated liver disease (IFALD). Although there is lack of unifying diagnosis, IFALD can present as cholestasis, steatosis, or fibrosis, with a prevalence that ranges between 5% and 43%. The development of IFALD tends to be multifactorial. Risk factors of IFALD can include those related to IF, inflammation/infection, and long-term parenteral nutrition. Some studies have shown a link between development of IFALD and ILE dose, especially if the dose is >1 g/kg/d, with high ω-6:ω-3 polyunsaturated fatty acid (PUFA) ratio and phytosterol content being theorized as some contributing factors. Thus, efforts have been made to use alternative oils (olive oil, medium-chain triglycerides, and fish oil) to reduce the soybean-oil content of ILE, which tends to be high in ω-6 PUFA and phytosterols. Although additional long-term clinical data are emerging, this strategy, as reviewed in the current manuscript, has shown to provide some benefit in both prevention and treatment of IFALD and other sequelae of HPN.

Current status of lipid emulsions in the prevention of intestinal failure-associated liver disease.

The current review provides a summary of available lipid products and discusses current literature and the limitations to the use of various lipid products for treatment and prevention of intestinal failure-associated liver disease (IFALD) in pediatric patients dependent on parenteral nutrition. Improvements in markers of cholestasis and liver function have been seen with minimizing soybean lipid, fish oil lipid, and mixed fish oil-containing lipid emulsions. Soybean-based lipid products are thought to be the biggest contributor to development of IFALD. Mixed fish oil-containing lipid emulsions are most promising for minimizing and improving IFALD. Several types of lipid-based products are available for parenteral nutrition. Newer products like the mixed fish oil-containing-based lipid emulsions, that closely mimic the lipid composition provided by enteral feeding, may impact prevention and treatment of IFALD. Limitations exist in the current literature regarding mixed fish oil-containing-based emulsions, as many of the studies were designed to show efficacy with regard to growth, not prevention or treatment of IFALD. Based on available literature, it is reasonable to make some recommendations with regard to product selection for lipid provision.

Impact of Clinical Use of Parenteral Lipid Emulsions on Bile Acid Metabolism and Composition in Neonatal Piglets.

Neonates with intestinal failure dependent on parenteral nutrition (PN) are at risk of intestinal failure-associated liver disease (IFALD). PN lipid composition relates to the risk of IFALD, but the mechanisms are poorly understood. We investigated the effects of soybean oil (SO), a mixed-lipid (ML) emulsion containing fish oil (FO), and a pure FO. We hypothesized FO-containing PN lipids would result in increased gene expression of canalicular bile acid transporters and a larger, more hydrophilic bile acid pool, predictive of increased bile flow. Neonatal piglets were allocated to receive 1 of SO, ML, or FO throughout 14 days of PN feeding. Relative expression of genes involved in bile acid synthesis and transport were determined through quantitative polymerase chain reaction. Bile secreted from the liver was collected and measured. Bile acid composition was determined using tandem mass spectrometry. Regression analysis was used to determine predictors of bile flow. PN reduced bile acid secretion (P < .001). FO-containing PN lipids were associated with greater expression of bile acid and organic solute transport genes (P < .05) and greater secretion of hydrophobic bile acids (P < .001). Farnesoid X receptor (P = .01), bile salt export pump (P < .01), multidrug resistant protein 2 (P < .01), and unconjugated hyocholic acid (P < .001) independently predicted bile flow. PN lipid modulation altered bile acid metabolism and composition. These alterations may explain the hepatoprotective effects of FO-containing PN lipids and support their use in the prevention and treatment of IFALD.

Correlation of Sonographic Findings and Liver Biochemistry Tests in Pediatric Patients with Intestinal Failure

Introduction: Intestinal failure-associated liver disease (IFALD) develops in children dependent upon long-term parenteral nutrition (PN). Laboratory and radiographic abnormalities are characteristic of the disorder. Sonographic findings (SF) include steatosis, edema, and biliary stones/sludge. Steatosis seems more prevalent in adults, while cholestasis is more prominent in children. IFALD can progress to fibrosis, cirrhosis, and end-stage liver disease. Abdominal ultrasound is a cost-effective and non-invasive modality that can be useful in examining the liver of patients with intestinal failure (IF). The aim of this study is to review liver SF and their correlation with liver biochemistry tests (LT) in pediatric patients with IF. Methods: We retrospectively reviewed the charts of 163 pediatric IF patients followed at our Center between 1998-2016. We specifically reviewed demographics, etiology of IF, SF and liver biochemistry tests. Results: Sixty eligible patients were included in this analysis (median age: 2.3 years, range: 1 month-18 years, 52% male). IF was caused by necrotizing enterocolitis (42%), gastrointestinal dysmotility (23%), intestinal atresia (13%), gastroschisis (8%) and volvulus (8%). Forty-six of 60 patients had elevated LT. Thirty-nine patients (85%) were cholestatic, and 35 patients (76%) had abnormal SF: splenomegaly (57%), hepatomegaly (54%), increased liver echogenicity (37%), gallbladder sludge (23%), cholelithiasis (17%), and heterogeneous liver (17%). Seven of 14 (50%) patients with normal LT had abnormal SF: splenomegaly (57%), cholelithiasis (43%), increased liver echogenicity (14%), and gallbladder sludge (14%). Conclusion: Abnormal SF were present in most pediatric IF patients with elevated LT and in half of the patients with normal LT. Increased liver echogenicity, suggestive of hepatic steatosis or edema, was more prevalent in children with IF than expected. Based on our single-center experience, we recommend the routine use of sonographic screening in pediatric patients with IF, regardless of LT, to achieve early detection and treatment of IFALD.

Omega-3 lipids for intestinal failure associated liver disease

Intestinal failure associated liver disease (IFALD) is one of the most common and devastating complications in infants with intestinal failure. Although multifactorial, its pathophysiology is clearly related to the administration of parenteral nutrition (PN), with a recent focus on the role of PN lipid emulsions. This paper will review the evidence for the use of omega-3 fatty acid PN lipid emulsions, which are proposed to have efficacy in the treatment of IFALD. Mechanisms explaining their effects will be considered as will future research directions.

Recent advances in the management of intestinal failure-associated liver disease

To summarize the current management of intestinal failure-associated liver disease (IFALD) by reviewing recent advances in our understanding of the condition and the effects of different therapeutic approaches. The importance of gastrointestinal length and continuity in the aetiology and treatment of IFALD has been demonstrated in both retrospective and interventional cohorts. A mechanism for the cholestatic effect of soy-based lipid has been described, and the clinical use of alternative lipid sources has demonstrated benefit. Prevention of IFALD has been shown with the use of erythromycin in neonates, and reversal of established IFALD has been demonstrated with isolated intestinal transplantation. A greater understanding of the mechanisms of IFALD has led to promising interventions to prevent and treat the condition. Other possible therapeutic targets require more formal evaluation, and further work is required to develop noninvasive tools for the assessment and prognosis of IFALD that will guide treatment and help in the selection of patients and timing of transplantation.