Predictors of failure of fish-oil therapy for intestinal failure-associated liver disease in children

Prathima Nandivada, Meredith A Baker, Paul D Mitchell, Alison A O'Loughlin, Alexis K Potemkin, Lorenzo Anez-Bustillos, Sarah J Carlson, Duy T Dao, Gillian L Fell, Kathleen M Gura, Mark Puder, Prathima Nandivada, Meredith A Baker, Paul D Mitchell, Alison A O'Loughlin, Alexis K Potemkin, Lorenzo Anez-Bustillos, Sarah J Carlson, Duy T Dao, Gillian L Fell, Kathleen M Gura, Mark Puder

Abstract

Background: Parenteral fish-oil (FO) therapy is a safe and effective treatment for intestinal failure-associated liver disease (IFALD). Patients whose cholestasis does not resolve with FO may progress to end-stage liver disease.

Objective: We sought to identify factors associated with the failure of FO therapy in treating IFALD to guide prognostication and referral guidelines.

Design: Prospectively collected data for patients treated with FO at Boston Children's Hospital from 2004 to 2014 were retrospectively reviewed. Resolution of cholestasis was defined as sustained direct bilirubin (DB) <2 mg/dL, and treatment failure as liver transplantation or death while DB was >2 mg/dL as of July 2015. Demographics, laboratory values, and medical history at FO therapy initiation were compared between patients who achieved resolution of cholestasis and those who failed therapy.

Results: Among 182 patients treated with FO, 86% achieved resolution of cholestasis and 14% failed therapy. Patients who failed therapy had median (IQR) lower birth weight [1020 g (737, 1776 g) compared with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation [20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk); P = 0.02] than patients whose cholestasis resolved. Patients who failed therapy had more advanced liver disease at therapy initiation than patients whose cholestasis resolved, as evidenced by lower median (IQR) γ-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L (76, 168 U/L); P < 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL) compared with 4.4 mg/dL (3.1, 6.6 mg/dL); P < 0.001], and a higher pediatric end-stage liver disease (PELD) score [22 (14, 25) compared with 12 (7, 15); P < 0.001]. A PELD score of ≥15, history of gastrointestinal bleeding, age at FO initiation ≥16 wk, presence of nongastrointestinal comorbidities, and mechanical ventilation at FO initiation were independent predictors of treatment failure.

Conclusions: Most infants with IFALD responded to FO therapy with resolution of cholestasis, and liver transplantation was rarely required. Early FO initiation once biochemical cholestasis is detected in parenteral nutrition-dependent patients is recommended. This trial was registered at clinicaltrials.gov as NCT00910104.

Keywords: Omegaven; cholestasis; fish oil; fish oil lipid emulsion; intestinal failure; intestinal failure–associated liver disease; parenteral fish oil; parenteral nutrition; parenteral nutrition–associated liver disease.

© 2016 American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Patient population (n = 212). Transplants included liver and multivisceral transplants. Three subjects who died after transplant were counted as transplants and not deaths. BCH, Boston Children’s Hospital; DB, direct bilirubin; FO, fish oil; IFALD, intestinal failure–associated liver disease.
FIGURE 2
FIGURE 2
Baseline anthropometric data. Sample sizes for cholestasis resolved and treatment failures, respectively, were n = 151 and n = 24 for WAZ, n = 125 and n = 21 for LAZ, and n = 122 and n = 18 for HCZ. Shown are box-and-whisker plots, where each box represents the IQR, the horizontal line represents the median, and the vertical whiskers extend ≤1.5 times the IQR. P values are from Wilcoxon’s rank-sum tests. HCZ, head circumference-for-age z score; LAZ, length-for-age z score; WAZ, weight-for-age z score.
FIGURE 3
FIGURE 3
Laboratory values at FO initiation. Sample sizes for cholestasis resolved and treatment failures, respectively, were (A) n = 156 and n = 25 for direct bilirubin; (B) n = 138 and n = 24 for AST, n = 146 and n = 23 for ALT, and n = 142 and n = 23 for GGT; (C) n = 138 and n = 20 for PELD; (D) n = 156 and n = 25 for platelets; and (E) n = 152 and n = 25 for INR. Shown are box-and-whisker plots, where each box represents the IQR, the horizontal line represents the median, and the vertical whiskers extend ≤1.5 times the IQR. P values are from Wilcoxon’s rank-sum tests. PELD = 4.8[ln(total bilirubin)] + 18.57[ln(INR) − 6.87[ln(albumin)] + 4.36 (if aged < 1 y) + 6.67 (if growth failure). ALT, alanine aminotransferase; AST, aspartate aminotransferase; FO, fish oil; GGT, γ-glutamyltransferase; INR, international normalized ratio; PELD, pediatric end-stage liver disease.
FIGURE 4
FIGURE 4
Severity of illness at FO initiation. Sample sizes for cholestasis resolved and treatment failures, respectively, were n = 147 and n = 26 for the percentage of patients who were mechanically ventilated, n = 149 and n = 25 for those requiring vasopressors, and n = 145 and n = 24 for those who were septic at the time of FO treatment initiation. FO, fish oil.

Source: PubMed

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