Publication: Johnson P, Phillips VL, Lamb N, Guo K, Zhao L, Brennan KM, et al. Effect of parenteral lipids on essential fatty acid deficiency in pediatric intestinal failure: A retrospective cohort study. J Parenter Enteral Nutr. 2024;48:793–801. DOI: 10.1002/jpen.2678
Reviewer: Tam Lac, MD, ASPEN Global Parenteral Nutrition Fellow 2024
Why is This Paper Important: Intestinal failure (IF) leads to “satellite” complications, including liver dysfunction and cholestasis, intestinal failure-associated liver disease (IFALD) (1,2,3). Historically, soybean oil lipid emulsion (SOLE) was the most accessible ILE in pediatrics (1). However, SOLE is associated with IFALD due to its high n-6 polyunsaturated fatty acids (PUFAs) and phytosterols content (2,3).
Linoleic acid (LA), a primary n-6 PUFA, converts to arachidonic acid (ARA), a precursor proinflammatory mediator, exacerbates inflammation, driving liver impairment, cholestasis, and fibrosis (1,2). Additionally, phytosterols disrupt bile acid homeostasis by antagonizing Farnesoid X receptors, impairing bile flow, and weakening antioxidant defenses (2,3). Standard SOLE dosage (2-3 g/kg/day) has been associated with IFALD development (1,3,5). Conversely, reduced SOLE dosage (1 g/kg/day) has shown significantly reduced cholestasis (1,3,5).
The benefit of diminishing lipid intake must be balanced against inadequate energy supply, particularly in newborns and premature infants requiring catch-up growth (3,5). Furthermore, the lowered SOLE dose may predispose essential fatty acid deficiency (EFAD) risk, diagnosed by an increased triene:tetraene ratio (TTR) (3,4,5). EFAD results from insufficient n-3 and n-6 FAs force oleic acid (n-9) converting to Mead acid, escalating TTR, indicating EFA depletion biochemically (3,4).
While weaning from parenteral nutrition is the goal of IFALD management, many pediatric patients cannot fully transition to enteral nutrition (1,3,5). Thus, alternative ILEs such as fish oil lipid emulsion (FOLE) and combination lipid emulsion (CLE) address SOLE’s weakness and mitigate IFALD risk (1,3). FOLE’s high amounts of n-3 PUFAs - alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) - reduce proinflammatory mediators and CLE’s balanced n3:n6 ratios, alpha-tocopherol, and minimized phytosterols improve hepatic function (1,2,3). Compared to SOLE, both improve inflammation and reduce oxidative stress (1,5). However, their modest EFA reservoir carries the risk of EFAD during long-term use (3,5).
All things considered, balancing sufficient energy intake and EFA supply while minimizing IFALD incidence is a clinical challenge (1,3,5).
Summary: This retrospective cohort study addressed an important gap in the literature by comparing ILEs and EFAD incidence with the hypothesis that CLE or FOLE is less associated with escalated EFAD incidence than SOLE in IF’s pediatric patients. It analyzed 144 FA profiles from 47 pediatric patients with IF across 10 years. The comparator groups were divided into SOLE, FOLE, and CLE.
EFAD incidence was investigated, as TTR ≥ 0.2. No recipients of ILE developed EFAD, except for one patient who developed EFAD after discontinuing ILE therapy.
There was no difference in the incidence of elevated TTR for patients receiving either CLE or FOLE compared to SOLE. Additionally, no statistically significant difference was observed in elevated TTR for those with bowel lengths above and below 45 cm. Importantly, compared with SOLE, there was no difference in the odds of cholestasis in CLE or FOLE recipients.
Finally, serum fatty acid profiles revealed substantial variations related to ILE. Compared with SOLE, patients receiving FOLE had significantly lower LA (p<0.001) and ARA (p=0.030) levels whereas supplemented CLE patients exhibited significantly higher ALA levels (p=0.035). Also, those complemented with SOLE had significantly lower EPA and DHA concentrations than other ILE groups (all comparisons p<0.001). Noticeably, the absence of ILE patients had significantly higher Mead acid levels than others (p<0.001).
Commentary: This study evaluated the theoretical concern of EFAD with CLE and FOLE in IF’s pediatric patients. CLE and FOLE, have demonstrated their strengths in diminished IFALD likelihood, and effective management of IFALD, respectively, supported by FDA approval. This study explored no discrepancy between the EFAD manifestations across ILE groups, suggesting that with proper dosing and monitoring, CLE and FOLE do not give rise to EFAD possibility despite their distinct compositions.
Strengths
Firstly, this study provides comprehensive statistical analysis with a robust, diverse sample and decade-long follow-up. Secondly, FOLE recruitment made this study unlike previous research (solely focused on CLE vs SOLE), widening our insights into the reliability and validity of differing ILEs for pediatric patients. Furthermore, examining detailed biochemical parameters, including LA, ALA, EPA, DHA, and Mead acid, is a plus due to transforming nuanced understandings of EFAD risk with different ILE applications. Additionally, this study supported previous findings that CLE’s lower soybean oil content does not contribute to the risk of EFAD for extended use. It reinforced the importance of appropriate doses and follow-up, as evidenced by diminished TTR, direct bilirubin, and EFAD resolution at higher CLE doses (2g/kg/day).
Limitations
This study’s single-center design reflected local practices, potentially limiting generalizability. As a retrospective study, it lacked individual enteral nutrition intervention and uniform lipid supplementation strategies, which could influence FA profile measurement. Also, it lacked uniformity in FA profile acquisition. Older SOLE recipients who likely had greater adipose reservoir and fewer EFAD outcomes, may have skewed results due to without novel ILE opportunities. Additionally, data regarding cholestatic episodes while administering similar ILE were missed. Also, measured triglyceride levels were absent. Finally, given low EFAD occurrence, this study could not evaluate the impact of specific lipid doses on EFAD risk.
Suggestions
Multicenter, prospective trials are critical to validate these findings and enhance nutritional care.
Further research should standardize FA profile methodologies and reduce variability. Additionally, FOLE’s low LA levels, while beneficial for IFALD management and liver transplantation prevention, may pose unclear influences on growth and cognition in premature infants with limited ability to convert ALA to DHA and LA to AA (1,3,5). Determining whether FOLE or CLE is appropriate for prolonged use in premature individuals is crucial (5).
Prior studies showed a paradoxical relationship between EFAD and hypertriglyceridemia (HTG) in preterm infants, where EFAD exacerbates HTG through de novo lipogenesis and fat mobilization (5). The clinical dilemma in neonatal lipid management occurs when HTG often prompts clinicians to alleviate ILE doses but this can exacerbate EFAD because of insufficient EFA intake (5). Addressing this gap between HTG and EFAD in premature infants is essential (3,5).
In conclusion, this study emphasizes the need for individualized ILE intervention with balancing IFALD prophylaxis, adequate energy, and EFA supply. To drive the nutrition field forward, future research should optimize ILE formulations with enhanced EFA content minimizing the trade-offs between lipid restriction and nutrition sufficiency, not only life-saving therapy but also ensuring optimal growth of vulnerable pediatric populations.
References:
- Hojsak I, Colomb V, Braegger C, Bronsky J, Campoy C, Domellöf M, et al. ESPGHAN Committee on Nutrition Position Paper. Intravenous Lipid Emulsions and Risk of Hepatotoxicity in Infants and Children: a Systematic Review and Meta-analysis. J Pediatr Gastroenterol Nutr. 2016 May;62(5):776-92. PMID: 26825766
- Calder PC, Waitzberg DL, College B, College Berthold. Intravenous Lipid Emulsions. 1 ed. Basel: S. Karger; 2014. World review of nutrition and dietetics, Vol.112. https://doi.org/10.1002/jpen.102
- Cober MP, Gura KM, Mirtallo JM, Ayers P, Boullata J, Anderson CR, et al. ASPEN lipid injectable emulsion safety recommendations part 2: Neonate and pediatric considerations. Nutr. Clin. Pract. 2021;36:1106–25. https://doi.org/10.1002/ncp.1077
- Baker MA, Mitchell PD, O’Loughlin AA, Potemkin AK, Anez-Bustillos L, Dao DT, et al. Characterization of Fatty Acid Profiles in Infants With Intestinal Failure–Associated Liver Disease. JPEN J Parenter Enteral Nutr. Jan 2018;42(1):71-7. DOI: 10.1002/jpen.102
- Chan AP, Strobel KM, Calkins KL. Essential Fatty Acid Deficiency in an Extremely Premature Infant With Intestinal Failure. JPGN Reports. 2021 May;2(2):e063. DOI: 10.1097/PG9.0000000000000063
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