OBJECTIVE The objective was to determine the safety and efficacy of a fish oil-based intravenous lipid emulsion (IFE) in the treatment of PNALD. SUMMARY AND BACKGROUND DATA Parenteral nutrition-associated liver disease (PNALD) can be a lethal complication in children with short bowel syndrome (SBS). IFE based on soybean oil administered with parenteral nutrition (PN) may contribute to its etiology. METHODS We performed an open-labeled trial of a fish-oil IFE in 42 infants with SBS who developed cholestasis (serum direct bilirubin > 2 mg/dL) while receiving soybean IFE. Safety and efficacy outcomes were compared with those from a contemporary cohort of 49 infants with SBS and cholestasis whose PN course included soybean IFE only. The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin ≤2 mg/dL). RESULTS Three deaths and 1 liver transplantation occurred in the fish oil cohort, compared to 12 deaths and 6 transplants in the controls (P=0.005). Among survivors not transplanted during PN, cholestasis reversed while receiving PN in 19/38 patients in the fish oil cohort vs. 2/36 patients in the controls. Based on Cox models, subjects receiving fish oil-IFE experienced reversal of cholestasis 6 times faster (95% CI=2.0,37.3) than those receiving soybean IFE. The provision of fish oil IFE was not associated with hypertriglyceridemia, coagulopathy, essential fatty acid deficiency. Moreover, hypertriglyceridemic events and abnormal INR levels were more common among controls. CONCLUSIONS Fish oil IFE is safe, may be effective in treating PNALD, and may reduce mortality and organ transplantation rates in children with SBS.

Objective The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids. Background Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (DHA, omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice. Design Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene-tetraene ratio (Mead acid/AA >0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD. Results No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene-tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when thirteen percent of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model. Conclusions When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Parenteral nutrition-associated liver disease (PNALD) is the most prevalent and most severe complication of long-term parenteral nutrition. Its underlying pathophysiology, however, largely remains to be elucidated. The currently approved parenteral lipid emulsions in the United States contain safflower or soybean oils, both rich in omega-6 polyunsaturated fatty acids (PUFAs). Mounting evidence indicates that the omega-6 PUFAs originating from plant oils in these lipid emulsions may play a role in the onset of liver injury. Fish oil-based lipid emulsions, in contrast, are primarily composed of omega-3 PUFAs, thus providing a promising alternative. The authors review the literature on the role of lipid emulsions in the onset of PNALD and discuss prevention and treatment strategies using a fish oil-based lipid emulsion. They conclude that a fish oil-based emulsion is hepatoprotective in a murine model of PNALD, and it appears to be safe and efficacious for the treatment of this type of liver disease in children. A prospective randomized trial that is currently under way at the authors' institution will objectively determine the place of fish oil monotherapy in the prevention of PNALD.

Objective The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of this study was to examine fatty acid profiles of patients receiving no enteral calories, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth. Methods Prospectively collected data from ten patients was reviewed for evidence of EFAD, defined as a triene:tetraene ratio greater than 0.2. Gestational age-adjusted Z-scores for length, growth and head circumference at baseline were compared to the corresponding Z-scores at time of censoring. All patients received PN with a fish oil-based lipid emulsion at 1 g.kg−1.day−1 as the sole source of fat calories for at least 1 month. The fish oil monotherapy was used under a compassionate use protocol. Results Median gestational age at time of birth was 35 weeks, and median age at the start of treatment was 3.5 months. After a median time of 3.8 months on exclusive PN and fish oil-based lipid emulsion, none of the patients developed biochemical or clinical evidence of EFAD. Z-scores were not statistically different, indicating no growth impairment. Median direct bilirubin levels improved in 9 patients from 6.8 mg/dL to 0.9 mg/dL (P=0.009). Conclusions When dosed appropriately, fish oil-based lipid emulsions contain sufficient amounts of essential fatty acids to prevent EFAD and sustain growth in patients completely dependent on PN.

Background Non-alcoholic fatty liver disease (NAFLD) results from over-consumption and is a significant and increasing cause of liver failure. The type of diet that is conducive to the development of this disease has not been established and evidence-based treatment options are currently lacking. We hypothesized that the onset of hepatic steatosis is linked to the consumption of a diet with a high fat content, rather than related to excess caloric intake. In addition, we also hypothesized that fully manifested hepatic steatosis could be reversed by reducing the fat percentage in the diet of obese mice. Methods C57Bl/6J male mice were either fed a purified rodent diet containing 10% fat or a diet with 60% of calories derived from fat. A pair-feeding design was used to distinguish the effects of dietary fat content and caloric intake on dietary-induced hepatic lipid accumulation and associated injury. Livers were analyzed by quantitative RT-PCR for lipid metabolism-related gene expression. Results After 9 weeks, mice on the 60% fat diet exhibited more weight gain, insulin resistance and hepatic steatosis, compared to mice on a 10% fat diet with equal caloric intake. Furthermore, mice with established metabolic syndrome at 9 weeks showed reversal of hepatic steatosis, insulin resistance and obesity when switched to a 10% fat diet for an additional 9 weeks, independent of caloric intake. Quantitative RT-PCR revealed that transcripts related to both de novo lipogenesis and increased uptake of free fatty acids were significantly upregulated in mice pair-fed a 60% fat diet, compared to 10% fat-fed animals. Conclusion Dietary fat content, independent from caloric intake, is a crucial factor in the development of hepatic steatosis, obesity and insulin resistance in the C57Bl/6J diet-induced obesity model caused by increased uptake of free fatty acids and de novo lipogenesis. In addition, once established, all these features of the metabolic syndrome can be successfully reversed after switching obese mice to a diet low in fat. Low fat diets deserve attention in the investigation of a potential treatment of patients with NAFLD.

Fish oil-derived emulsions have been demonstrated to reverse preexisting PNALD and to prevent and treat essential fatty acid deficiency. Its ability to prevent PNALD is currently under investigation. Although the mechanism has yet to be fully understood, the advantages of fish oil-based lipid emulsions over soybean oil-based lipid emulsions seen to date suggest that fish oil-based emulsions would be better suited for use in long-term parenteral nutrition.

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Parenteral nutrition is known to cause liver injury in babies. The aim of this study is to investigate the effects of different lipid emulsions on parenteral nutrition-associated cholestasis in infants. In addition, there may be a relationship between the lipid emulsion and triglyceride levels. Furthermore, triglyceride levels may correlate with direct bilirubin and albumin, as markers of liver impairment and nutritional status. Patients with parenteral nutrition-associated cholestasis who were treated with a fish oil-based lipid emulsion (n=18) were prospectively followed for triglyceride, direct bilirubin, and albumin levels and compared to patients who were maintained on a soy-based lipid emulsion (n=59). Triglyceride levels decreased in the fish oil cohort from a mean of 140 mg/dL at week 0 to 40 mg/dL at week 20, but remained unchanged at approximately 140 mg/dl in the soybean cohort. Triglyceride levels of patients treated with fish oil declined over time, while those receiving soybean oil did not. Also, changes in triglyceride levels over time were directly correlated with direct bilirubin and inversely related to albumin levels. These findings may indicate an added benefit of reduced triglyceride levels for patients treated with fish oil and this effect coincides with markers for improved liver function and nutritional status.