Infants, particularly premature infants, may survive without a lifelong dependence on PN with as little as 11 cm of initial bowel length, due in part to rapidly growing bowel and adaptation during this time.24
However, in the PN dependent infant, hepatic injury frequently occurs before bowel adaptation and growth is complete and full EN intake has been achieved. Therefore, the goal is to develop an effective nutritional regimen that allows for bowel growth and adaptation before the onset of end stage liver disease. The significance of such a treatment strategy are considerable given the fact that PNALD has a mortality rate as high as 90% in those children unable to be weaned off PN within a year of diagnosis.25
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 decrease in direct bilirubin, more frequently and more rapidly than the comparison group. Previous experience suggests that in most instances, reversal of cholestasis could only occur after PN is discontinued and full EN has been established.
The etiology of PNALD may be due to use of soybean-based emulsions, secondary to pro-inflammatory metabolites of omega-6 fatty acids,26
coupled with a decreased hepatic clearance of the parenteral lipid.27
Unlike fish oil emulsions, soybean derived lipids contain phytosterols (eg stigmasterol, b-sitosterol, and campesterol) that are linked with impairment of biliary secretion.28
Past and very recent studies have suggested that phytosterols may be the "hepatoxic" or "cholestatic" component of soybean derived lipid emulsions This multitude of factors results in a cholestatic, steatotic liver that is particularly susceptible to inflammatory insults (e.g. bloodstream infections, surgery, hepatotoxic medications).29
In turn, repeated liver injury results in fibrosis, cirrhosis, and progresses to end stage liver disease. Fish oil-based emulsions address these problems on several fronts. Omega-3 fatty acid metabolites present in fish oil are less involved in the inflammatory response26
and animal models have shown that parenteral fish oil does not impair biliary secretion and may prevent steatosis.19,30,31
Comparisons based on a historical cohort could result in bias. Since previous medical records were less complete, more follow-up data was missing in this group. A delay in 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 soybean oil cohort were due to poorer management of care, resultant from historical trends. For example, mortality in the soybean oil cohort, uniformly recorded over time, did not increase and was consistent with experiences from other centers. Furthermore, the rate of increase of bilirubin in both groups when all patients were receiving soybean oil fat emulsions 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 due to several prognostic factors, including gestational age. The impact of these biases should be reduced when estimating adjusted effect in multiple regressions. Although clinical improvement in the fish oil cohort could theoretically be in part due to lower doses of 1g/kg/day than what is typically used in pediatric PN, several patients in the fish oil cohort developed cholestasis while receiving only 1g/kg/day of soybean oil. Although the fear of developing EFAD from the use of OmegavenR as monotherapy is real when doses are less than 1g/kg/day are used, adding back soybean oil at a dose of 1g/kg/day in combination with OmegavenR 1g/kg/day may actually hinder reversal of cholestasis as demonstrated in a recently published papers.32,33
In fact, in that case series, soybean oil emulsions were stopped when patients failed to improve.32,34
This practice of combining the 2 products may have even contributed to the progression of liver disease as evidenced by the need for 3/12 subjects to undergo a liver-intestine transplant. Although 9/12 subjects did experience complete and sustained resolution of their cholestasis, 5/9 patients had the IntralipidR
stopped requiring rescue with OmegavenR
given as monotherapy in order to see improvement. Only 4/12 patient’s cholestasis resolved on the combination therapy. Similar to our experience, no patients in that case series died due to PNALD. Moreover, it may be possible that even higher doses of OmegavenR could be used although we have not explored this possibility.33
In conclusion, we have demonstrated that utilization of fish oil-based emulsion in infants dependent on PN as a life-sustaining measure may reverse cholestasis and fatal liver disease. More importantly, we have not observed any deleterious side effects of treatment. These benefits may be due to the absence of soybean oil, the pharmacologic effects of fish oil, the reduction of lipid dose, the ability to increase enteral nutrition, or a combination of all these factors. Ideally, a prospective randomized controlled trial comparing fish oil emulsions to soybean emulsions in the treatment of established PNALD should be conducted, but this type of study would be difficult to conduct as some may consider it unethical to perform a study where children with preexisting PN liver injury could potentially be randomized 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 institiution to assess the efficacy of fish oil-based emulsions in the prevention of cholestasis in which subjects are randomized to either conventional soybean oil emulsion or fish oil emulsion at a goal dose of 1g/kg/day at the start of their PN course.