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Safety and Efficacy of a Fish-Oil–Based Fat Emulsion in the Treatment of Parenteral Nutrition–Associated Liver Disease

^a Departments of Pharmacy
^b Division of Gastroenterology and Nutrition
^c Surgery
^d Clinical Research Program
^e Department of Nursing, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts

	ABSTRACT

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BACKGROUND. Parenteral nutrition–associated liver disease can be a progressive and fatal entity in children with short-bowel syndrome. Soybean-fat emulsions provided as part of standard parenteral nutrition may contribute to its pathophysiology.

METHODS. We compared safety and efficacy outcomes of a fish-oil–based fat emulsion in 18 infants with short-bowel syndrome who developed cholestasis (serum direct bilirubin level of >2 mg/dL) while receiving soybean emulsions with those from a historical cohort of 21 infants with short-bowel syndrome who also developed cholestasis while receiving soybean emulsions. The primary end point was time to reversal of cholestasis (3 consecutive measurements of serum direct bilirubin level of 2 mg/dL).

RESULTS. Among survivors, the median time to reversal of cholestasis was 9.4 and 44.1 weeks in the fish-oil and historical cohorts, respectively. Subjects who received fish-oil–based emulsion experienced reversal of cholestasis 4.8 times faster than those who received soybean emulsions and 6.8 times faster in analysis adjusted for baseline bilirubin concentration, gestational age, and the diagnosis of necrotizing enterocolitis. A total of 2 deaths and 0 liver transplantations were recorded in the fish-oil cohort and 7 deaths and 2 transplantations in the historical cohort. The provision of fish-oil–based fat emulsion was not associated with essential fatty acid deficiency, hypertriglyceridemia, coagulopathy, infections, or growth delay.

CONCLUSIONS. Parenteral fish-oil–based fat emulsions are safe and may be effective in the treatment of parenteral nutrition–associated liver disease.

Key Words: -3 • cholestasis • parenteral nutrition associated liver disease • fish oil • parenteral nutrition

Abbreviations: PN—parenteral nutrition • PNALD—parenteral nutrition–associated liver disease • EN—enteral nutrition • CHB—Children's Hospital Boston • SBS—short-bowel syndrome • IQR—interquartile range • CI—confidence interval

Parenteral nutrition (PN) provides an alternative for patients unable to absorb adequate enteral nutrients, usually secondary to insufficient intestinal length or function. Diagnoses include motility disorders, intestinal resections, atresias, necrotizing enterocolitis, and inflammatory bowel disease. In 2002, the National Institute of Diabetes and Digestive and Kidney Diseases stated that 20000 individuals in the United States were supported by PN for intestinal failure.¹ Before the PN era, these patients commonly died of malnutrition.²

PN contains macronutrients in their most elemental form and is commonly administered with fat emulsions to prevent essential fatty acid deficiency and to provide nonprotein calories. Although PN is life saving, it is associated with hepatic dysfunction, including biochemical (ie, elevated bilirubin and transaminases) and histologic alterations (ie, steatosis, steatohepatitis, cholestasis, fibrosis, and cirrhosis).³ These abnormalities, which may worsen with prolonged administration, are more prevalent in the pediatric population.⁴ Approximately 30% to 60% of children develop hepatic dysfunction while receiving long-term PN.⁵

Although the pathology of PN-associated liver disease (PNALD) has been well described,⁶ its etiology, prevention, and treatment are poorly understood. Risk factors include prolonged PN use, prematurity, frequent surgical procedures, lack of enteral intake, and sepsis.⁷ Early feeding may slow progression and, if not cirrhotic, cholestasis may be reversible once PN is discontinued and full enteral nutrition (EN) is established.⁸ Partial EN may also be protective.⁹ However, treating cholestasis by discontinuing PN is difficult, because it may result in starvation if EN is not absorbed. Other treatment options, including metronidazole, ursodeoxycholic acid, and choline, have had moderate success.¹⁰ In refractory hepatic failure, liver with or without small-bowel transplantation remains the only option. Considering modern graft and patient 5-year survival rates for liver/small-bowel and small-bowel-alone transplants are in the range of 43% to 75% and 57% to 75% respectively, alternative medical and surgical strategies for short-bowel syndrome (SBS) and PNALD are needed.¹¹

The etiology of PNALD is unknown, but a contributing factor may be the intravenous fat emulsion. Currently in the United States, fat emulsions are derived from either soybean/safflower or soybean oils, both rich in -6 fatty acids (Table 1). In a murine model, fish-oil emulsions prevented steatosis, a precursor of PNALD, as well as reversed preexisting disease, likely via improved triglyceride clearance coupled with antiinflammatory properties.¹² This emulsion contains -3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid, an eicosanoid precursor. Increased synthesis of eicosapentaenoic acid-derived mediators may promote antiaggregatory and antiinflammatory effects. This emulsion also contains arachidonic acid, an -6 fatty acid. In a case series where 2 patients with cholestasis were treated with fish-oil–based fat emulsions, serum bilirubin levels normalized.¹³ Patients tolerated this therapy well, and no adverse reactions attributed to its use were observed.

	METHODS

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Patients
Between September 2004 and August 2006, under a compassionate treatment protocol at Children's Hospital Boston (CHB), 18 infants receiving PN with soybean emulsions who developed cholestasis were treated with fish-oil emulsions and prospectively followed. Eligibility requirements included serum direct bilirubin level of 2 mg/dL and predicted PN duration of >30 days because of congenital or acquired gastrointestinal disease. Children with other liver diseases (ie, cystic fibrosis, inborn metabolic errors, and hepatitis C) were excluded.

A historical cohort of 30 infants with SBS, who were PN dependent for >90 days and treated at CHB from 1986 to 1996, was reviewed for comparison purposes.¹⁴ Outcomes of 21 eligible subjects (2 consecutive direct bilirubin levels of >2 mg/dL) were included.

Study Treatment
In the fish-oil cohort, the soybean-based emulsion (Intralipid, Fresenius Kabi AG, Bad Homburg vdh, Germany) was discontinued, and treatment with fish-oil–based emulsion (Omegaven, Fresenius Kabi AG) was started. For the first 2 days of treatment, patients received fish-oil emulsions at 0.5 g/kg per day to assess tolerance and were progressed to a maintenance dosage of 1 g/kg per day over 12 hours. The 12-hour infusion time was used to minimize waste because of Centers for Disease Control and Prevention requirements that source containers of lipid emulsion be changed every 12 hours. Dosing was based on the previous use of fish-oil emulsions as monotherapy.¹⁵ The comparison group received either Lyposin II (Hospira, Lake Forest, IL) or Intralipid, which are soybean/safflower and soybean emulsions, respectively. Doses ranged from 1 to 4 g/kg per day over 24 hours.

Study Outcomes
The primary study outcome was time to reversal of cholestasis, defined as time to the first of 3 consecutive serum direct bilirubin measurements of 2 mg/dL. Laboratory values were prospectively measured at approximately weekly intervals. The historical cohort had all of the available tests retrospectively recorded and measured approximately biweekly. Safety outcomes, including fatty acid and coagulation profiles, growth (weight-for-age z scores), and bloodstream infections, were systematically recorded only in the experimental group. Laboratory values and nutritional intake were retrospectively recorded 2 months before baseline, defined as the date that fish-oil emulsion began for the fish-oil cohort or as the date of the second of 2 consecutive direct bilirubin values of >2 mg/dL for the comparison group.

Statistical Analysis
Statistical significance of baseline differences between the 2 groups was assessed via t tests when reporting means (or Wilcoxon tests when reporting medians) and ² tests when reporting proportions (or Fisher's exact tests when warranted). Primary analysis of efficacy of fish-oil–based emulsions was based on comparisons of time to reverse cholestasis while still receiving PN and included only those who did not die or undergo liver transplantation. Secondary analysis of efficacy included all of the patients, with censor criteria of death and transplantation. In both analyses, patients who did not reverse cholestasis by PN cessation or by end of follow-up were censored, and bilirubin levels were imputed by using linear interpolation, if 2 consecutive measurements were missing. Twenty-three bilirubin levels (of a total of 528 recorded measurements) were imputed. Four bilirubin levels were imputed in the fish-oil group and 19 in the soybean group. Results were comparable with and without imputation.

Kaplan-Meier survival curves were estimated for the time to reverse cholestasis using the product limit estimator and compared through log-rank tests. Crude and adjusted hazard ratios were estimated using proportional hazard models. In regression models, after including the treatment effect, variables were forced in for gestational age and direct bilirubin at enrollment, and these additional confounders were considered: gender, birth weight, diagnosis of necrotizing enterocolitis and/or atresia, multiple surgical diagnoses, baseline PN and EN energy intake (kilojoules per kilogram of body weight per day), and daily carbohydrate, fat, and protein intake (grams per kilogram per day). The additional confounders were retained if they appreciably affected the coefficient of treatment or if the P value for the likelihood ratio test was <.05. Survival analyses were also performed assuming that the PN effect could last 2 months by defining reversal of cholestasis as 3 direct bilirubin levels of 2 mg/dL 2 months after PN cessation. In these analyses, patients were censored 2 months after being weaned off PN. In patients receiving fish-oil emulsions, adverse events were summarized for the period before the beginning of therapy, 0 to 30 days after, and >30 days after. Primary analysis was based on comparisons between the pretherapy period and 30 days after.

All of the P values were 2 sided. Analyses were performed with SAS 9.1 (SAS Institute, Inc, Cary, NC) and S-plus 7 (Insightful, Seattle, WA).

Because Omegaven is not yet approved for use in the United States, Food and Drug Administration approval was obtained. This study was also approved by the CHB institutional review board. Informed consent was also obtained.

	RESULTS

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At baseline, several characteristics of the experimental group pointed to a more severe extent of illness compared with the historical cohort (Table 2), although differences were not statistically significant. These included shorter gestation, fewer enteral calories, and higher direct bilirubin level on enrollment. Nutritional intake at baseline was comparable; enteral intake was greater in the historical cohort. Results at baseline were comparable when analyzing only survivors. Of note, 81% of patients in the historical cohort were enrolled after 1992.

In all 39 of the subjects, although levels of direct bilirubin at baseline were higher in the fish-oil cohort, trajectories of direct bilirubin were similar before (week –8 to 0) and 4 weeks after baseline (Fig 1). After this time, and particularly after week 8, direct bilirubin levels decreased in the fish-oil group but not in the historical cohort. In subjects who received higher mean doses of fish oil during therapy, that is, larger than the 80th percentile for mean dose in the fish oil group or between 0.87 and 0.92 mg/kg per day, the decaying trajectory was equivalent to subjects who received lower doses, that is, 0.87 mg/kg per day (Fig 2). In the soybean-emulsion group, subjects who received a mean dose of lipid from baseline to the end of PN equivalent to the higher dose of the fish oil took longer to reverse cholestasis. The mean dose of soybean oil these subjects received was below the 20th percentile of the mean daily soybean oil dose, that is, 0.67 to 0.98 mg/kg per day.

View larger version (12K): [in this window] [in a new window]   FIGURE 1 Direct bilirubin trajectories over time (weeks from baseline) for the fish-oil (A) and soybean (B) cohorts. Box plots represent the distribution of direct bilirubin levels in each 2-week interval plotted at the end of the interval, except for the bar at week 0, which represents only direct bilirubin measures at baseline. The number of observations contained in each 2-week interval is in parentheses. The solid bar within the box represents the median value; upper boundary of the box, the 75th percentile; lower boundary of the box, 25th percentile. Whiskers extend to the most extreme observation within 1.5 IQR units of the 25th and 75th percentiles.

View larger version (10K): [in this window] [in a new window]   FIGURE 2 Individual direct bilirubin trajectories over time (weeks from baseline) for children who received higher (A) and lower (B) mean daily doses of fish oil during treatment, that is, below and above the cutoff of 0.87 g/kg per day (value corresponding with the 80th percentile). C, The trajectories of direct bilirubin levels are plotted for children in the soybean-emulsion group receiving an equivalent mean daily dose of lipid from baseline to the end of parenteral nutrition, that is, <0.98 (20th percentile of the soybean-emulsion group) and >0.67.

View larger version (9K): [in this window] [in a new window]   FIGURE 3 Kaplan-Meier curves with the proportion of subjects who reversed cholestasis according to different days in the fish-oil and historical cohorts.

View this table: [in this window] [in a new window]   TABLE 3 Increase in the Rate (as Measured by the Hazard Ratio) of Reversing Cholestasis (3 Consecutive Direct Bilirubin Levels of 2 mg/dL) While Receiving PN in the Fish-Oil Cohort Compared With the Historical Cohort

	DISCUSSION

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Infants, particularly premature infants, may survive without a lifelong dependence on PN with as little as 11 cm of initial bowel length,¹⁶ attributed in part to rapidly growing bowel during this time. However, PNALD frequently occurs before bowel adaptation and growth are complete and EN can be tolerated. Therefore, it is a matter of what occurs first: bowel development or end-stage liver disease. The sequelae are significant considering that PNALD has a mortality rate as high as 100% in those children unable to be weaned off PN within a year of diagnosis.¹⁷ Our results suggest that fish-oil–based emulsions may reverse PNALD when used in place of standard soybean emulsions. The experimental group reversed cholestasis, as measured by a decrease in direct bilirubin level, more frequently and more rapidly than the comparison group. The median time to reverse cholestasis was 9 weeks in the fish-oil and 44 weeks in the historical cohort, effectively halting the progression of PNALD and providing a chance to develop enteral tolerance and PN independence. Previous experience suggests that, in most cases, a reversal of cholestasis occurs after PN is discontinued and EN has been established,⁸ but this experimental group consistently deviated from these norms. In comparison with the control group, these patients at baseline had lower enteral intake. However, once the serum bilirubin levels decreased (4 weeks after the start of treatment), enteral intake increased, which may be attributed, in part, to enhanced bile excretion and improved nutrient absorption. In addition, fewer deaths and transplantations were observed in the fish-oil group.

More intriguing is the finding that 3 patients in the experimental arm experienced normalization of their serum bilirubin levels with <10% enteral intake, whereas no patient in the control group was able to achieve similar outcomes. We are not aware of this ever occurring at our institution until the use of this therapy. In addition, our results suggest that reversal of cholestasis in the fish-oil group occurred regardless of the lipid dose. A similar decay of trajectories of direct bilirubin in the higher and lower mean doses of fish oil was observed for nearly all of the subjects, particularly those who did not die. Moreover, subjects in the fish-oil group experience reversal of their cholestasis faster than subjects in the soybean-emulsion group, when comparisons were done only among subjects in the fish-oil and soybean oil cohorts who received equivalent mean doses of fat emulsion from baseline to the end of the study, These results, however, should be interpreted with caution, because the sample size of this subgroup was small.

The administration of fish-oil–based emulsions seems safe. After 4 weeks of therapy, only 1 patient displayed biochemical, not clinical, evidence of essential fatty acid deficiency (triene/tetraene ratio: >0.2). In this case, the patient's fish-oil emulsion had been discontinued, whereas EN was increased, in the presence of fat malabsorption; biochemical essential fatty acid deficiency occurred only after the patient had not received fish-oil emulsions for 3 weeks. The fish-oil emulsion was actually resumed to correct the observed deficiency. There was no increase in bleeding events, no change in growth, and no increase in infection rate. Two children receiving fish-oil–based emulsions died from causes unrelated to treatment. One died from aspiration pneumonia and sepsis. Another died when care was withdrawn because of irreparable cardiopulmonary disease.

The etiology of PNALD may be because of the use of soybean-based emulsions, secondary to proinflammatory metabolites of -6 fatty acids,¹⁸ and decreased hepatic clearance of the parenteral lipid.¹⁹ Soybean-derived lipids contain phytosterols (eg, stigmasterol, b-sitosterol, and campesterol) that are linked with impairment of biliary secretion.²⁰ Past and very recent studies have suggested that phytosterols may be the "hepatoxic" or "cholestatic" component of soybean-derived lipid emulsions, with recent molecular mechanisms of phytosterols being suggested.^21,22 It has also been suggested that -6 fatty acids may contribute to impaired immunologic function.²³ This multitude of factors results in a cholestatic, steatotic liver that is especially susceptible to inflammatory insults (eg, bloodstream infections, surgery, and hepatotoxic medication).²⁴ In turn, repeated liver injury results in fibrosis, cirrhosis, and end-stage liver disease. Fish-oil–based emulsions address these problems on several fronts. -3 fatty acid metabolites are less involved in the inflammatory response,¹⁸ and animal models have shown that parenteral fish oil does not impair biliary secretion and may prevent steatosis.^12,25,26 Hence, the liver is not predisposed to inflammatory insult, and liver injury can be prevented.

Comparisons based on a historical cohort could result in bias. Because previous medical charts were less complete, more follow-up data were missing in this group. A delay in the time to reverse cholestasis could result from missing bilirubin measurements and result in overestimating the effect of fish-oil–based emulsions. To minimize these biases, bilirubin levels were imputed for certain data points. It is unlikely that worse outcomes in the historical cohort were because of poorer management of care, resultant from historical trends. For example, mortality in the historical cohort, uniformly recorded over time, did not increase. Furthermore, the rate of increase of bilirubin level in both groups was similar. Underestimation of fish-oil–induced reversal of cholestasis could result from enrollment under a compassionate protocol, because the patients were more severely ill and were higher risk because of several prognostic factors, including gestational age. The impact of these biases should be reduced when estimating adjusted effect in multiple regressions.

	CONCLUSIONS

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We have demonstrated that the use of fish-oil–based emulsion in infants who depend on PN as a life-sustaining measure may reverse cholestasis and fatal liver disease. More importantly, we have not observed any deleterious adverse effects of treatment. These benefits may be because of the absence of soybean oil or because of the pharmacologic effects of fish oil; however, this hypothesis is difficult to test because of the need to provide essential fatty acids in parenterally fed patients. Ideally, a prospective randomized, controlled trial comparing fish-oil emulsions with soybean emulsions in the treatment of established PNALD should be conducted, but this type of study would be difficult to conduct, because some may consider it unethical to perform a study where children with preexisting PN liver injury could potentially be randomly assigned to a treatment group in which they would continue to receive a soybean oil–based parenteral lipid emulsion. A prospective, randomized trial is underway at our institution to assess the efficacy of fish-oil–based emulsions in the prevention of cholestasis in which in infants who have never been exposed to either type of lipid emulsion are randomly assigned to either conventional soybean oil emulsion or fish-oil emulsion at the start of their PN course.

	ACKNOWLEDGMENTS

 
Dr Puder is funded by National Institutes of Health grant DK069621-01 and the Children's Hospital Boston Surgical Foundation (Boston, MA). Dr Lee is funded by the Daland Fellowship in Clinical Investigation from the American Philosophical Society (Philadelphia, PA). Mr Strijbosch is funded by Trustfonds Erasmus Universiteit Rotterdam (Rotterdam, Netherlands), Dr Saal van Zwanenberg Stichting (Oss, Netherlands), VSB fonds (Den Haag, Netherlands), and Michaël van Vloten fonds (Venray, Netherlands).

We give special thanks to Sharon Collier, Clifford Lo, Melanie Connolly, Shelby Wilson, and Sharon Silverman of the Division of Gastroenterology and Nutrition, Children's Hospital Boston, and Carine Lenders of Boston Medical Center.

	FOOTNOTES

 
Accepted Oct 24, 2007.

Address correspondence to Mark Puder, MD, PhD, Children's Hospital Boston, 300 Longwood Ave, Fegan 3, Boston, MA 02115. E-mail: mark.puder{at}childrens.harvard.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Gura, K. M. Articles by Puder, M. PubMed PubMed Citation Articles by Gura, K. M. Articles by Puder, M. Related Collections Gastrointestinal Tract

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