This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT: We propose to determine the efficacy of a novel intravenous lipid preparation in the management of infants with cholestasis. In this study, we aim to determine if changing from an omega-6 predominant product to an omega-3 predominant product will decrease the severity of existing cholestasis related to the use of intravenous nutrition (total parenteral nutrition, TPN). Omegaven, an omega-3 fatty acid-based lipid emulsion, will be intravenously infused at a dose of 1gm/kg/day until the infant is weaned from parenteral nutrition and for no longer than three months. This is an open-label study with no placebo needed. At the end of three months, the condition of the infant is evaluated, and Omegaven therapy may continue for an additional two months if needed. If the infant develops hypertriglyceridemia, the condition will be treated, and therapy will continue if the infant receives a transplant. HYPOTHESIS: Changing from an omega-6 predominant product to an omega-3 predominant product will decrease the severity of existing cholestasis related to the use of total parental nutrition in infants. Objective: To determine the short-term safety and obtain preliminary data related to the short-term efficacy of a novel intravenous lipid preparation in the management of infants with cholestasis who have a high risk of death or needing transplant. Primary endpoints include: death or transplant, number of episodes of sepsis, total bilirubin 60 days after enrollment and frequency of essential fatty acid deficiency. Secondary endpoints include: time to full feeds, evidence of rickets and resolution (maximum alkaline phosphatase activity) and growth in weight, length and head circumference.
SPECIFIC AIMS :
We aim to determine the efficacy of a novel intravenous lipid preparation in the management of infants with cholestasis. The experiment will help us to determine if changing from an omega-6 predominant product to an omega-3 predominant product will decrease the severity of existing cholestasis related to the use of intravenous nutrition (total parenteral nutrition). BACKGROUND AND SIGNIFICANCE Parenteral nutrition (PN) provides intravenous nutritional supplementation for patients unable to absorb adequate enteral nutrients secondary to insufficient intestinal length or function. PN contains the macronutrient building blocks of the human diet in their most elemental forms (amino acids and dextrose) and is commonly administered with a lipid emulsion to avoid essential fatty acid deficiency and to provide a calorically dense source of non-protein calories. In addition, PN contains the essential micronutrients (electrolytes, trace elements, and vitamins) to provide an optimal nutritional regimen. Before the development of PN in the late 1960 s, patients with insufficient gastrointestinal absorptive function commonly died of starvation and subsequent complications of malnutrition. Today, more than 30,000 patients are permanently dependent on parenteral nutrition for survival. However, PN continues to be associated with hepatic injury that occurs at an unpredictable rate and includes both biochemical, i.e., elevated serum aminotransferase and alkaline phosphatase, and histologic alterations such as steatosis, steatohepatitis, lipidosis, cholestasis, fibrosis, and cirrhosis. These abnormalities, which may worsen with the duration of PN administration, is more prevalent in the pediatric population. Additional risk factors for this condition include prematurity, low birth weight, long-term use of PN, the lack of concomitant enteral intake, sepsis, and multiple operative procedures. Although the pathological features of PN-induced liver injury have been well described, the etiology, prevention, and treatment of this complication are not well understood. Multiple hypotheses exist to explain the pathogenesis of PN-induced liver injury including altered gut hormonal profiles, the propensity for bacterial translocation in the absence of enteral intake, intestinal stasis resulting in the reduced clearance of hepatotoxic bile acids, and direct deficiencies or toxic components of the PN solution itself resulting in excessive glucose calorie uptake, excessive lipid infusion, or nutritional deficiencies such as essential fatty acid deficiency. None of these theories has been confirmed consistently. The etiology of PN-associated hepatotoxicity is currently considered multifactorial. Available treatment options for this disease process are limited and have achieved moderate success at best. Care of the PN-dependent patient is focused on gradually increasing enteral caloric intake as the residual bowel adapts allowing PN to be discontinued. In fact, it has been shown both experimentally and clinically that partial enteral nutrition, when tolerated, helps to protect against the development of PN-associated liver injury. In severe cases of refractory hepatic failure, liver transplantation with or without accompanying small bowel transplantation remains the only treatment option. Role of Intravenous Fat Emulsion on PN Associated Liver Disease: Recent evidence demonstrates that lipids are metabolized differently depending on their route of administration. Enteral lipids are absorbed by the enterocyte in the small bowel mucosa in the form of a micelle and packaged into chylomicrons which are released into the portal venous system for ultimate uptake and disposal in the liver. Once in the bloodstream, these particles rapidly acquire apolipoproteins from circulating high-density lipoproteins and can subsequently be metabolized by the liver. The emulsified particles of commercially made and intravenously administered lipid emulsions, such as Intralipid?, mimic the size and structure of chylomicrons, but differ in their content. In contrast to chylomicrons, artificial lipid particles primarily contain essential fatty acids and omega-6 triglycerides and are devoid of cholesterol or protein. Recent studies suggest that these omega-6 fatty acid-containing emulsions are dependent on lipoprotein lipase, apolipoprotein E, and low-density lipoprotein receptors for clearance, and are metabolized with less lipolysis and release of essential fatty acids than are chylomicrons. In fact, it appears that they may be cleared as whole particles by tissues other than the liver. These factors may account for the increased incidence of steatohepatitis associated with the intravenous administration of Intralipid?. The mechanism of clearance of omega-3 fatty acid containing lipid emulsions is unknown, but appears to be largely independent of the pathways identified above. Furthermore, omega-3 fatty acid solutions have been shown to decrease de novo lipogenesis, prevent or attenuate PN-induced hepatosteatosis in rats and guinea pigs and ameliorate the severity of high-fat diet-induced hepatosteatosis in rats. In addition, omega-3 fatty acids can interfere with the arachidonic acid pathway of inflammation. They can displace arachidonic acid from tissue fatty acid pools, thereby reducing the availability for eicasanoid-synthesizing enzymes and inflammation.
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