Failure of Resolution of Portal Fibrosis during Omega-3 Fatty Acid Lipid Emulsion Therapy in Two Patients with Irreversible Intestinal Failure Jason S. Soden, MD, Mark A. Lovell, Kristin Brown, David A. Partrick, and Ronald J. Sokol Parenteral omega-3 fatty acid lipid emulsions have been evaluated for their potential role in reversing intestinal fail- ure-associated liver disease. We report our experience using Omegaven in 2 patients with irreversible intestinal fail- ure and intestinal failure-associated liver disease. Despite biochemical and histologic improvement in cholestasis, both patients had persisting, significant portal fibrosis on liver biopsy. (J Pediatr 2010;156:327-31) I ntestinal failure associated liver disease (IFALD) is an im- portant cause of morbidity and mortality in pediatric pa- tients receiving long-term parenteral nutrition (PN). The distinct etiology of IFALD remains unknown and likely in- volves multiple factors in the patient with intestinal failure, including post-surgical anatomy, intestinal stasis, or both and altered permeability, sepsis, and excesses, deficiencies, and/or contaminants attributed to the PN. 1 Currently, there is no established therapy to treat IFALD other than discon- tinuation of PN and advancing enteral feedings. 2-6 Recently, Omegaven (Fresenius Kabi, Bad Hamburg, Ger- many), a fish oil-based lipid emulsion, has been reported as a potential therapy for treating IFALD 7-10 This novel therapy replaces traditional (soybean-based) lipid solutions with a fish oil-ased product that is rich in omega-3 fatty acids. Re- cent reports have demonstrated reversal of biochemical indi- cators of cholestasis in patients with IFALD compared with historical control subjects. 8 We report our experience using fish oil-based lipid emulsion in 2 patients with irreversible intestinal failure. Both patients demonstrated persistence of portal fibrosis, progression of por- tal fibrosis, or both while receiving fish oil-based lipid emul- sion therapy, despite improvement in markers of cholestasis. Case Summaries Case 1 A 38-week gestational age male infant with long segment Hirshsprung disease (HD) underwent an end jejunostomy at 3 weeks of age, which left <20 cm bowel distal to ligament of Trietz in continuity. PN was initiated in the first week of life (100-110 kcal/kg/day: 14%-20% dextrose concentration in PN, 1.5-2 g/kg/day protein, and 1-3 g/kg/day omega-6- based lipid [Intralipid, Fresenius Kabi]). The patient had 4 episodes of catheter-associated infections in the first few months of life. The patient was referred for combined intestinal and liver transplant (LITx) evaluation and was listed for transplanta- tion at 2.5 months of age. During the patient’s first 6 months of life, progressive cholestasis developed. Results of a liver biopsy at 4 months demonstrated stage 2 fibrosis, portal inflammation, and marked hepatocellular, canalicular cholestasis, and other histological features consistent with IFALD (Figure 1). At 6 months, the patient had an episode of sepsis and an elevated serum (trough) triglycerides level (536 mg/dL), and omega-6-based lipid was held (from an an- tecedent dose of 1 g/kg/day). Immediately thereafter, as part of a compassionate use protocol, omega-6-based lipid was discontinued, and fish oil-based lipid emulsion was started (1 g/kg/day). The patient made slow progress with enteral feeding volumes and remains receiving >60% parenteral ca- loric support at age 24 months. The Table shows laboratory data before and after fish oil-based lipid emulsion initiation. Because of persistent elevation in aspartate aminotransfer- ase and alanine aminotransferase levels, a percutaneous liver biopsy was obtained at 17 months, the results of which showed stage 3 to 4 hepatic fibrosis (Figure 1), despite re- duction in inflammation and cholestasis. Ongoing portal hypertension was suggested by the platelet count that had not yet normalized in the 12 months after resolution of bio- chemical cholestasis (Table), and hepatic ultrasound scan- ning results that demonstrated progressive splenomegaly (data not shown). Case 2 A 32-week gestational age female infant with microvillous in- clusion disease (MVID), confirmed with electron microscopy of duodenal biopsy, was treated with PN in the first month of life (100-110 kcal/kg/day: 14%-20% dextrose concentra- tion in PN, 1.5-2 g/kg/day protein, and 1-3 g/kg/day From the Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics (J.S., K.B., R.S.), Department of Pathology, Department of Pediatric Surgery (M.L.), and Clinical Translational Research Center (R.S.), University of Colorado Denver School of Medicine and The Children’s Hospital, Aurora, CO Presented in part at the World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition, Iguazu, Brazil (August 2008), and Children’s Digestive Health and Nutrition Foundation/North American Society for Pediatric Gastroenterology, Hep- atology and Nutrition Meeting, San Diego, California (November 2008). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.08.033 HD Hirschsprung disease IFALD Intestinal failure-associated liver disease LITx Liver transplant MVID Microvillous inclusion disease PN Parenteral nutrition 327