Vincent E. de Meijer

Parenteral Fish Oil Improves Outcomes in Patients with Parenteral Nutrition Associated Liver Injury

Objective:The objective was to determine the safety and efficacy of a fish oil-based intravenous lipid emulsion (ILE) in the treatment of parenteral nutrition-associated liver disease (PNALD). Summary and Background Data:PNALD can be a lethal complication in children with short bowel syndrome (SBS). ILE 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-based ILE in 42 infants with SBS who developed cholestasis (serum direct bilirubin >2 mg/dL) while receiving soybean oil-based ILE. Safety and efficacy outcomes were compared with those from a contemporary cohort of 49 infants with SBS and cholestasis whose PN course included soybean ILE 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 with 12 deaths and 6 transplants in the soybean oil cohort (P = 0.005). Among survivors not transplanted during PN, cholestasis reversed while receiving PN in 19 of 38 patients in the fish oil cohort versus 2 of 36 patients in the soybean oil cohort. Based on Cox models, subjects receiving fish oil-based ILE experienced reversal of cholestasis 6 times faster (95% CI: 2.0–37.3) than those receiving soybean oil-based ILE. The provision of fish oil-based ILE was not associated with hypertriglyceridemia, coagulopathy, or essential fatty acid deficiency. Moreover, hypertriglyceridemic events and abnormal international normalized ratio levels were more common among controls. Conclusions:Fish oil-based ILE is safe, may be effective in treating PNALD, and may reduce mortality and organ transplantation rates in children with SBS.

The essentiality of arachidonic acid and docosahexaenoic acid.

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 (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 13% 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.

Dietary fat intake promotes the development of hepatic steatosis independently from excess caloric consumption in a murine model.

Nonalcoholic fatty liver disease results from overconsumption 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. C57BL/6J male mice were fed either 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 reverse transcriptase polymerase chain reaction for lipid metabolism-related gene expression. After 9 weeks, mice on the 60%-fat diet exhibited more weight gain, insulin resistance, and hepatic steatosis compared with 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 reverse transcriptase polymerase chain reaction revealed that transcripts related to both de novo lipogenesis and increased uptake of free fatty acids were significantly up-regulated in mice pair-fed a 60%-fat diet compared with 10%-fat-fed animals. 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 nonalcoholic fatty liver disease.

Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition Dependent Patients

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 the present study was to examine fatty acid profiles of patients receiving no enteral energy, while completely dependent on PN and an intravenous fish oil–based lipid emulsion, for onset of EFAD and maintenance of growth. Patients and Methods: Prospectively collected data from 10 patients were reviewed for evidence of EFAD, defined as a triene:tetraene ratio >0.2. Gestational age–adjusted z scores for length, growth, and head circumference at baseline were compared with the corresponding z scores at time of censoring. All of the patients received PN with a fish oil–based lipid emulsion at 1 g · kg−1 · day−1 as the sole source of fat energy for at least 1 month. The fish oil monotherapy was used under a compassionate use protocol. Results: Median gestational age at the 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 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 who are completely dependent on PN.

Comparison of 5 intravenous lipid emulsions and their effects on hepatic steatosis in a murine model

BACKGROUND Plant-based intravenous lipid emulsions have been shown to contribute to parenteral nutrition-associated liver disease (PNALD). There is mounting evidence that fish oil-based emulsions may prevent this liver injury. This study compares 5 emulsions with different fat compositions and their effect on hepatic steatosis, one of the first hits in PNALD. METHODS C57BL/6J mice were placed on a fat-free diet and randomized into 5 equal groups. Each group received one of the commercially available intravenous lipid emulsions (Intralipid [Baxter/Fresenius Kabi, Deerfield, Ill], Liposyn II [Hospira Inc, Lake Forest, Ill], ClinOleic [Baxter/Clintec Parenteral SA, Cedex, France], SMOFlipid [Fresenius Kabi, Bad Homburg, Germany], or Omegaven [Fresenius Kabi Deutschland GmbH]) or normal saline. Liver enzymes, degree of steatosis, and fatty acid compositions were analyzed after 19 days. RESULTS Intralipid, Liposyn II, ClinOleic, and SMOFlipid groups all demonstrated moderate steatosis with hepatic fat contents of 17.4%, 21.9%, 22.5%, and 12.6%, respectively. Omegaven mice, however, had normal livers. Saline control mice developed biochemical evidence of essential fatty acid deficiency (EFAD). Lipid supplementation with Intralipid, Liposyn II, and Omegaven prevented the onset of biochemical EFAD, whereas administration of ClinOleic and SMOFlipid did not. CONCLUSION The fish oil-based lipid emulsion Omegaven prevented hepatic steatosis and EFAD in this murine model. ω-3 fatty acids may be efficacious in preventing PNALD and should be explored in the development of novel lipid emulsions.

Parenteral fish oil monotherapy in the management of patients with parenteral nutrition-associated liver disease.

OBJECTIVES To update knowledge on the management of parenteral nutrition-associated liver disease (PNALD) and to review the clinical data on the use of parenteral fish oil for reversal of PNALD. DATA SOURCES A literature review was conducted by searching the MEDLINE database (May 1, 2009) using the keywords parenteral nutrition-associated liver disease, fish oil, omega-3, Omegaven, and lipid emulsion. STUDY SELECTION All articles reporting clinical cases with the use of parenteral fish oil for management of PNALD. DATA EXTRACTION Three reviewers independently analyzed the epidemiological, clinical, and treatment data of the articles. DATA SYNTHESIS Six case reports (10 patients) and 2 cohort studies (12 and 18 patients) were analyzed. CONCLUSIONS 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.

Broad-Spectrum Matrix Metalloproteinase Inhibition Curbs Inflammation and Liver Injury but Aggravates Experimental Liver Fibrosis in Mice

Background Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-α-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury. Methodology/Principal Findings Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4 was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-α receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-α receptors exhibited an 80% reduction of serum ALT, confirming the hepatoprotective effects of Marimastat via the TNF-signaling pathway. Conclusions/Significance Inhibition of MMP and TACE activity with Marimastat during chronic CCl4 administration counterbalanced any beneficial anti-inflammatory effect, resulting in a positive balance of collagen deposition. Since effective inhibition of MMPs accelerates fibrosis progression, MMP inhibitors should be used with caution in patients with chronic liver diseases.

Innovative parenteral and enteral nutrition therapy for intestinal failure

Children with intestinal failure (IF) suffer from insufficient intestinal length or function, making them dependent on parenteral nutrition (PN) for growth and survival. PN and its components are associated with many complications ranging from simple electrolyte abnormalities to life-threatening PN-associated liver disease, which is also called intestinal failure-associated liver disease (IFALD). From a nutrition perspective, the ultimate goal is to provide adequate caloric requirements and make the transition from PN to full enteral nutrition (EN) successful. Upon review of the literature, we have summarized the most effective and innovative PN and EN therapies for this patient population. Antibiotic-coated catheters and antibiotic or ethanol locks can be implemented, as they appear effective in reducing catheter-related infection and thus further reduce the risk of IFALD. Lipid emulsions should be given judiciously. The use of an omega-3 fatty acid-based formulation should be considered in patients who develop IFALD. Trophic feeding is important for intestinal adaptation, and EN should be initiated early to help wean patients from PN. Long-term management of children with IF continues to be an emerging field. We have entered uncharted territory as more children survive complications of IF and IFALD. Careful monitoring and individualized management to ensure maintenance of growth while avoiding complications are the keys to successful patient outcomes.

Parenteral fish oil as monotherapy improves lipid profiles in children with parenteral nutrition-associated liver disease.

BACKGROUND Parenteral nutrition (PN) is a life-saving therapy but has been associated with dyslipidemia. Because fish oil has been shown to have positive effects on lipid profiles, the authors hypothesize that a parenteral fish oil lipid emulsion will improve lipid profiles in children who are PN dependent. METHODS The authors examined the lipid profiles of a unique cohort of 10 children who were exclusively administered a fish oil-based lipid emulsion while on PN for a median duration of 14 weeks. Longitudinal data analysis with a generalized estimating equations approach was used to determine the sterol and bilirubin levels based on duration of the fish oil-based lipid emulsion. RESULTS After 14 weeks of fish oil monotherapy, children had a 24% increase in high-density lipoprotein. Compared to baseline, serum low-density lipoprotein, very low-density lipoprotein, total cholesterol, and triglyceride levels all significantly decreased by 22%, 41%, 17%, and 46%, respectively. Eight children had their bilirubin improved with a decreased direct bilirubin from 6.9 mg/dL (range, 4.4-10.7) at baseline to 2.3 mg/dL (range, 1.3-4.0) after 14 weeks, and a decrease in total bilirubin from 8.7 mg/dL (range, 5.5-13.7) to 3.8 mg/dL (range, 2.2-6.5). CONCLUSION A fish oil-based lipid emulsion used as monotherapy in children who exclusively depended on PN for survival was associated with significant improvement in all major lipid panels as well as improvement of hyperbilirubinemia. Parenteral fish oil may be the preferred lipid source in children with dyslipidemia.

Parenteral fish oil as monotherapy for patients with parenteral nutrition-associated liver disease.

Dear Editor, We read the paper by Diamond et al. [1] which provided a brief overview of the use of fish oil in patients with short bowel syndrome and parenteral nutrition-associated liver disease (PNALD). In their article, the authors discourage the use of the fish oil-based Omegaven (Fresenius Kabi, Bad Homburg, Germany) as the sole lipid source in patients on parenteral nutrition, which in our opinion is unwarranted. At our institution, we use Omegaven at a dose of 1 g kg day as the sole source of lipid for the treatment of infants with PNALD under a compassionate use protocol [2, 3]. The author’s group from Canada mix Omegaven with the standard soy bean oil-based lipid emulsion Intralipid (Fresenius Kabi, Bad Homburg, Germany), as they believe that such a balanced mix makes more sense physiologically than an emulsion composed primarily of either omega-6 fatty acids (e.g., Intralipid ) or omega-3 fatty acids (e.g., Omegaven ). Unlike Intralipid , however, the lipid component in Omegaven is based on fish oil that contains arachidonic acid, eicosapentaenoic acid, and docosapentaenoic acid, but also contains 0.1–0.7% linoleic acid, which has been shown to be sufficient to prevent essential fatty acid deficiency (EFAD) [4]. In fact, the first reported clinical use of Omegaven as monotherapy was for the reversal of EFAD in a patient allergic to soy based lipid emulsions [5]. Second, the authors do not recommend Omegaven as the sole lipid source in patients on parenteral nutrition because of concerns for malnutrition related to a decrease in overall fat intake and increase in carbohydrate uptake, reasoning that this can hypothetically lead to increased lipogenesis, worsening coagulopathy, and EFAD. The authors themselves, however, substituted Intralipid with Omegaven in short bowel syndrome patients with advanced liver disease and concluded that Omegaven has the ability to restore liver function without complications or mortality [1]. Furthermore, they ‘‘rescued’’ eight of 12 patients with Omegaven alone [1, 6]. In a prospective case series of 18 consecutive patients, which was published in the journal Pediatrics the month prior to the authors’ manuscript submission, we have demonstrated that patients on Omegaven experienced from adequate to improved growth and did not have signs of coagulopathy or EFAD 30 days after initiation of therapy [3]. We have since treated more than 90 patients with cholestasis at our institution with Omegaven as the sole lipid source under an ongoing compassionate use protocol, and none have experienced malnutrition, nor developed EFAD (unpublished data). We agree that the optimal omega-6/omega-3 ratio remains to be defined, and that a well designed prospective randomized controlled trial is imperative to evaluate the safety and efficacy of omega-3 fatty acids for long-term parenteral nutrition. At our institution, such a trial is now underway [7]. Based on the need to ‘‘rescue’’ patients that received a mixture of Intralipid and Omegaven , and the lack of adverse events in the Omegaven treated patients, V. E. de Meijer J. A. Meisel H. D. Le M. Puder Department of Surgery, Vascular Biology Program, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA e-mail: Vincent.DeMeijer@Childrens.Harvard.Edu