Cholestasis Reversal (Phase ll): Efficacy of lV Fish Oil

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DESCRIPTION (provided by applicant): Parenteral nutrition (PN) solutions are life saving in patients with surgical gastrointestinal diseases. However, the use of PN in pediatric populations, especially premature infants, is frequently associated with liver injury that may ultimately result in liver failure that can lead to transplantation and/or death. Studies suggest that soybean oil containing intravenous fat emulsions (IFE) may be a major contributing factor. Recent experience suggests that discontinuing soybean based IFE and switching to a product comprised of omega-3 fatty acids derived from fish oils (Omegaven) may be effective in reversing preexisting PN associated liver disease through a combination of factors, including improved triglyceride clearance coupled with anti-inflammatory properties. In 2002, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) stated that 20,000 individuals in the US were supported by PN for intestinal failure and of these, approximately 30-60% of children develop hepatic dysfunction after receiving prolonged courses of PN. This project plans to study 30 such pediatric patients over a 3 year period with preexisting liver disease due to PN use. The primary aim is to assess the efficacy of the fish oil fat emulsion in reversing cholestasis due to PN use. Using an open label study design, patients with PN cholestasis will have the conventional soybean oil lipid emulsion stopped and be treated with the fish oil based IFE. Time to reversal of cholestasis of subjects treated with the fish oil will be compared to 60 similar subjects (contemporary historical controls) who continued to receive soybean based IFE after developing cholestasis. Other hepatic, growth, and safety outcomes will be also assessed. Based on preliminary results, it would be difficult to perform a prospective randomized trial with these patients. Although the proposed study is not a randomized trial, it is thought that sufficient evidence could be generated that would result in FDA approval of an lFE such as Omegaven.