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AJCN. First published ahead of print August 10, 2016 as doi: 10.3945/ajcn.116.137083.

Predictors of failure of fish-oil therapy for intestinal failure–associated


liver disease in children1,2
Prathima Nandivada,3,6 Meredith A Baker,3,6 Paul D Mitchell,4 Alison A O’Loughlin,3 Alexis K Potemkin,3
Lorenzo Anez-Bustillos,3 Sarah J Carlson,3 Duy T Dao,3 Gillian L Fell,3 Kathleen M Gura,5 and Mark Puder3*
3
Vascular Biology Program and Department of Surgery, 4Clinical Research Center, Biostatistics Core, and 5Department of Pharmacy, Boston Children’s
Hospital, Boston, MA

ABSTRACT INTRODUCTION
Background: Parenteral fish-oil (FO) therapy is a safe and effective Parenteral nutrition (PN)7 is a lifesaving therapy for children
treatment for intestinal failure–associated liver disease (IFALD). with intestinal failure caused by insufficient bowel length or
Patients whose cholestasis does not resolve with FO may progress to function (1, 2). PN affords infants who would otherwise die of
end-stage liver disease. starvation or malnutrition a chance to grow and develop. With
Objective: We sought to identify factors associated with the failure time, intestinal adaptation may occur, allowing children to absorb
of FO therapy in treating IFALD to guide prognostication and re- nutrients from an enteral diet such that PN can be discontinued (3).
ferral guidelines. Long-term PN treatment is limited by potentially serious compli-
Design: Prospectively collected data for patients treated with FO at cations, including liver disease. Up to 75% of infants who require
Boston Children’s Hospital from 2004 to 2014 were retrospectively PN for 60 d develop intestinal failure–associated liver disease
reviewed. Resolution of cholestasis was defined as sustained direct (IFALD) (4). In the early 2000s, infants with IFALD followed for
bilirubin (DB) ,2 mg/dL, and treatment failure as liver transplan- $2 y had a 26% transplant and 27% mortality rate (4).
tation or death while DB was .2 mg/dL as of July 2015. Demo- IFALD is characterized initially by intrahepatic cholestasis,
graphics, laboratory values, and medical history at FO therapy initiation which can occur within 2 wk of initiating PN, and then by pro-
were compared between patients who achieved resolution of chole- gressive fibrosis and ultimately cirrhosis over the course of several
stasis and those who failed therapy.
months (5, 6). Without transitioning to full enteral feedings, cir-
Results: Among 182 patients treated with FO, 86% achieved resolu- rhosis may progress to end-stage liver disease, with death from
tion of cholestasis and 14% failed therapy. Patients who failed therapy sepsis or portal hypertension (4, 7, 8).
had median (IQR) lower birth weight [1020 g (737, 1776 g) compared Parenteral fish-oil (FO) therapy has been shown to be a safe
with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation
and effective treatment for IFALD, with successful resolution of
[20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk);
biochemical cholestasis and avoidance of liver transplantation in
P = 0.02] than patients whose cholestasis resolved. Patients who failed
85% of infants (9–13). However, PN-dependent patients in whom
therapy had more advanced liver disease at therapy initiation than pa-
cholestasis is not resolved with FO therapy may progress to end-
tients whose cholestasis resolved, as evidenced by lower median (IQR)
stage liver disease, requiring liver transplantation or resulting in
g-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L
death. To date, there are no methods to our knowledge for pre-
(76, 168 U/L); P , 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL)
dicting which infants will fail to respond to FO therapy. Thus, we
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
aimed herein to identify early patient factors associated with
with 12 (7, 15); P , 0.001]. A PELD score of $15, history of gastro- 1
intestinal bleeding, age at FO initiation $16 wk, presence of nongas- Supported by Boston Children’s Hospital, the Corkin and Maher Family
Fund, the Joshua Ryan Rappaport Fellowship, and NIH grants T32 HL007734-22,
trointestinal comorbidities, and mechanical ventilation at FO initiation
F32 HD071715-01, and F32 DK104525-01.
were independent predictors of treatment failure. 2
Supplemental Tables 1 and 2 are available from the “Online Supporting
Conclusions: Most infants with IFALD responded to FO therapy Material” link in the online posting of the article and from the same link in
with resolution of cholestasis, and liver transplantation was rarely the online table of contents at http://ajcn.nutrition.org.
6
required. Early FO initiation once biochemical cholestasis is detected These authors contributed equally to this work.
in parenteral nutrition–dependent patients is recommended. This *To whom correspondence should be addressed. E-mail: mark.puder@
trial was registered at clinicaltrials.gov as NCT00910104. Am J childrens.harvard.edu.
7
Clin Nutr doi: 10.3945/ajcn.116.137083. Abbreviations used: BCH, Boston Children’s Hospital; DB, direct bili-
rubin; FO, fish oil; IFALD, intestinal failure–associated liver disease; INR,
international normalized ratio; LAZ, length-for-age z score; PELD, pediatric
Keywords: cholestasis, fish oil, fish oil lipid emulsion, intestinal end-stage liver disease; PN, parenteral nutrition.
failure, intestinal failure–associated liver disease, Omegaven, parenteral Received April 21, 2016. Accepted for publication July 14, 2016.
fish oil, parenteral nutrition, parenteral nutrition–associated liver disease doi: 10.3945/ajcn.116.137083.

Am J Clin Nutr doi: 10.3945/ajcn.116.137083. Printed in USA. Ó 2016 American Society for Nutrition 1 of 8

Copyright (C) 2016 by the American Society for Nutrition


2 of 8 NANDIVADA ET AL.

subsequent failure of FO therapy to guide prognostication and determine the presence of cholestasis, severity of hepatic injury,
patient referral guidelines. and status of hepatic synthetic function, the following laboratory
values were recorded from the medical record: total bilirubin, DB,
g-glutamyltransferase, aspartate aminotransferase, alanine ami-
METHODS notransferase, international normalized ratio (INR), albumin, and
Patients platelet count. From these data, the pediatric end-stage liver
disease (PELD) score was calculated as PELD = 4.8[ln(total
We retrospectively reviewed prospectively collected data from bilirubin)] + 18.57[ln(INR)] – 6.87[ln(albumin)] + 4.36 (if aged
children with IFALD treated with parenteral FO (Omegaven; ,1 y) + 6.67 (if growth failure), where growth failure was defined
Fresenius Kabi) at Boston Children’s Hospital (BCH) between 1 as a length or weight z score ,22 per United Network for Organ
January 2004 and 31 December 2014. The study protocol was Sharing guidelines. The PELD score is used to measure illness
approved by our institutional review board. IFALD was defined severity in the allocation of livers to pediatric candidates (#11 y)
as serum DB .2 mg/dL for 2 consecutive weeks with no other and is a validated predictor of mortality from end-stage liver
causes of liver disease. FO monotherapy was administered in- disease; however, it cannot distinguish irreversible from reversible
travenously at a dose of 1 g $ kg21 $ d21 as previously described liver disease (16–18). Two patients aged .11 y at FO initiation
in accordance with the study protocol at BCH for the compas- were excluded from the analysis of independent predictors of
sionate use of FO through the Food and Drug Administration treatment failure.
(9). Patients whose cholestasis did not resolve with FO therapy Charts were reviewed for medical history and severity of illness
were identified and defined as treatment failures. Resolution of at the time of FO initiation. Medical and surgical diagnoses were
cholestasis was defined as sustained DB ,2 mg/dL. Treatment recorded. Patent ductus arteriosus was recorded if it required
failure was defined as undergoing liver or multivisceral trans- medical or surgical treatment. Lung disease of prematurity was
plantation or death while the DB was .2 mg/dL as of 31 July recorded if a diagnosis of respiratory distress syndrome, chronic
2015. Patients who initiated FO therapy at another institution lung disease, bronchopulmonary dysplasia, or pulmonary hem-
were excluded from analysis because of the inconsistent avail- orrhage was made in a patient who was born prematurely and
ability of baseline laboratory values and medical history. Pa- required a surfactant, intubation, or prolonged intubation. Intra-
tients currently under active therapy for cholestasis were also ventricular hemorrhage was recorded for grade $3 (19). Non-
excluded (defined as DB .2 mg/dL as of 31 July 2015). gastrointestinal comorbidities were categorized as pulmonary,
cardiovascular, neurologic, genetic or chromosomal, hematologic
Study endpoints or oncologic, endocrinologic, renal or genitourinary, and traumatic
(data not shown). History of gastrointestinal bleeding at any time
The primary aim of this study (NCT00910104; clinicaltrials. before FO therapy initiation was recorded. Mechanical ventila-
gov) was to determine predictors of treatment failure of paren- tion, vasopressor treatment, and sepsis at the time of FO therapy
teral FO in children treated for IFALD from 2004 to 2014. Patient initiation were recorded. History of mechanical ventilation, va-
demographics, anthropometrics, hospital transfer status, labo- sopressor treatment, and sepsis that had resolved by the time FO
ratory values, and medical history at initiation of FO therapy were therapy was initiated were not recorded.
compared between patients who achieved resolution of chole-
stasis with FO therapy and those who failed therapy.
Baseline weight, length, and head circumference measurements
were used to calculate age- and sex-adjusted z scores for 175 sub- Statistics
jects, with growth measurements obtained [weight-for-age z score, Categorical data were reported as frequencies (percentages)
length-for-age z score (LAZ), and head circumference-for-age z and compared across groups by Pearson’s chi-square test or
score] with the use of methods appropriate to baseline age: Olsen Fisher’s exact test when the expected cell count was ,5 in $1
et al. (14) if ,40 wk corrected gestational age (n = 71), WHO if cell. Unadjusted continuous data were reported as medians
aged ,2 y (n = 92), or CDC (15) if aged .2 y (n = 12). To (IQRs) and compared across groups by Wilcoxon’s rank-sum

TABLE 1
Independent predictors of treatment failure1
Multiple imputation
Cholestasis Treatment Complete case (n = 146) (n = 180)
resolved failure
Characteristic (n = 127) (n = 19) OR (95% CI) P OR (95% CI) P

PELD score $15


2
30 (24) 13 (68) 5.7 (1.8, 17.9) 0.003 6.9 (2.4, 20.2) 0.0004
History of gastrointestinal bleeding 22 (17) 8 (42) 5.1 (1.5, 17.7) 0.01 4.5 (1.5, 13.6) 0.009
Age $16 wk 46 (36) 13 (68) 6.9 (1.9, 25.0) 0.003 4.9 (1.5, 15.3) 0.007
Mechanical ventilation 16 (13) 7 (37) 6.7 (1.5, 29.5) 0.01 4.2 (1.3, 14.0) 0.02
Nongastrointestinal comorbidity 62 (49) 14 (74) 3.2 (0.9, 11.7) 0.08 3.5 (1.0, 11.9) 0.05
1
Values are n (%) unless otherwise indicated. Results are from logistic regression and are shown for the complete-case
model and after imputation to replace missing covariate data. INR, international normalized ratio; PELD, pediatric end-
stage liver disease.
2
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).
PREDICTORS OF FISH-OIL THERAPY FAILURE 3 of 8

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.

test. Logistic regression was used to determine independent cholestasis. Twenty-six (14%) patients failed therapy [8 trans-
predictors of treatment failure and was restricted to 8 variables, plantations (6 multivisceral and 2 liver) and 18 IFALD-associated
with P , 0.10 on unadjusted analysis (birth weight, PELD deaths]. Of note, although they were not deemed treatment fail-
score, age and LAZ at FO initiation, mechanical ventilation, ures, 9 patients whose cholestasis resolved subsequently died of
history of gastrointestinal bleed, sepsis, and nongastrointestinal nonhepatic causes. Liver failure with sepsis was the most com-
comorbid condition). Birth weight, PELD score, and age at FO mon cause of death among treatment failures, whereas sepsis was
initiation were not linear in the logit and were dichotomized. the most common cause among those who reversed on FO but
Penalized likelihood estimation was used to overcome the po- subsequently died (Supplemental Table 1, Table 2).
tential for sample bias caused by the small number of subjects A total of 118 patients (65%) were transferred from another
with treatment failure (20, 21). A final model obtained by institution with pre-existing IFALD compared with 64 patients
stepwise regression resulted in 5 predictors: a PELD score $15 (35%) who developed IFALD at BCH. A higher proportion of
at FO initiation, history of gastrointestinal bleeding, initiation patients transferred to BCH with IFALD-failed FO therapy than
of FO at $16 wk of age, presence of nongastrointestinal those who developed IFALD at BCH; however, this difference
comorbidities at FO initiation, and mechanical ventilation at FO
initiation. This model fit well as assessed by the Hosmer-Lemeshow
statistic (P = 0.65) (22). Multiple imputation was used to investigate TABLE 2
the sensitivity of the results to missing data. Results from both the Causes of death
complete-case and multiple imputation models were reported as n (%)
ORs with 95% CIs. The conventional threshold of P , 0.05 was
Never reversed (treatment failure) 18
used to establish statistical significance. The presence of gastroin- Liver failure and:
testinal comorbidities at FO initiation was borderline significant by Sepsis 5 (26)
multiple imputation and is included in Table 1. All tests of sig- Redirection of care in setting of respiratory failure 3 (17)
nificance were 2-sided, and all data were analyzed with SAS ver- Redirection of care in setting of intracranial 3 (17)
sion 9.3 (SAS Institute Inc.). hemorrhage
Redirection of care in setting of poor neurologic 2 (11)
prognosis
RESULTS Redirection of care in setting of multiple congenital 2 (11)
malformations
Outcomes of parenteral FO therapy Hemorrhage 2 (11)
Chronic graft-versus-host disease 1 (6)
A total of 188 patients treated with parenteral FO for IFALD at Cholestasis resolved with fish oil but patient subsequently died 9
BCH from 1 January 2004 to 31 December 2014 were identified Sepsis 3 (33)
(Figure 1). Six patients were excluded because they transferred Sudden cardiac arrest at home 2 (22)
care or were weaned off PN before cholestasis had been resolved Metastatic neuroblastoma 2 (22)
but did not fail FO therapy (i.e., undergo transplant or die). Of Respiratory failure or arrest 1 (11)
the remaining 182 patients, 156 (86%) achieved resolution of Unknown 1 (11)
4 of 8 NANDIVADA ET AL.
TABLE 3
Unadjusted predictors of treatment failure1
Overall Cholestasis resolved Treatment failure
Characteristic Unknown (n = 182) (n = 156) (n = 26) P

Males 0 104 (57) 88 (56) 16 (62) 0.62


Caucasians 0 126 (69) 111 (71) 15 (58) 0.17
Hispanics 2 35 (19) 31 (20) 4 (15) 0.57
Birth gestational age, wk 9 32 (26, 36) 32 (26, 36) 31 (26, 34) 0.30
Birth weight, g 17 1475 (800, 2305) 1608 (815, 2438) 1020 (737, 1776) 0.03
Extremely low birth weight (,1 kg) 17 57 (35) 47 (33) 10 (48) 0.18
Birth length, cm 80 41.7 (34.0, 46.5) 42.0 (34.5, 47.0) 36.2 (32.0, 41.5) 0.05
Age at PN start, d 6 1.0 (0.0, 2.0) 1.0 (0.0, 2.0) 1.0 (0.0, 2.0) 0.59
Age at FO start, wk 7 12.7 (7.7, 24.9) 11.7 (7.3, 21.4) 20.4 (9.9, 38.6) 0.02
#14 d FO therapy 3 6 (3) 4 (3) 2 (8) 0.18
Ever exclusive enteral feeding 2 33 (18) 27 (17) 6 (24) 0.41
Any prior operations 1 173 (96) 149 (96) 24 (96) 1.00
Stoma2 3 88 (49) 77 (50) 11 (44) 0.58
Duodenostomy 3 9 (5) 9 (6) 0 (0) 0.36
Jejunostomy 3 42 (23) 38 (25) 4 (16) 0.34
Ileostomy 3 37 (21) 31 (20) 6 (24) 0.66
Colostomy 3 4 (2) 3 (2) 1 (4) 0.46
1
Values are n (%) or medians (IQRs) unless otherwise noted. P values are from Pearson’s chi-square or Fisher’s exact
tests if categorical and Wilcoxon’s rank-sum test otherwise. FO, fish oil; PN, parenteral nutrition.
2
Stoma location, if present, at time of FO therapy initiation (most proximal if multiple).

was not statistically significant [20/118 (17%) compared with 62% (13/21) with DB 10–14.9 mg/dL, and 45% (5/11) with DB
6/64 (9%)]. $15 mg/dL (P , 0.0001 by Cochran-Armitage test for trend; data
not shown). Patients who failed FO therapy had more advanced
Influence of patient demographics liver disease at the time of FO initiation than patients who did not
fail therapy, as evidenced by higher DB [10.4 mg/dL (IQR: 7.5,
Patients were 57% male and 69% Caucasian (Table 3). The 14.1 mg/dL) compared with 4.4 mg/dL (IQR: 3.1, 6.6 mg/dL);
median gestational age was 32 wk (IQR: 26, 36 wk), and the P , 0.0001]; lower platelet counts [67 3 103/mL (IQR: 46, 104 3
median birth weight was 1475 g (IQR: 800, 2305 g). The median 103/mL) compared with 194 3 103/mL (IQR: 125, 301 3 103/mL);
age at PN initiation was 1 d (IQR: 0, 2 d), and the median age at FO P , 0.0001]; higher INR [1.27 (IQR: 1.16, 1.61) compared with
initiation was 12.7 wk (IQR: 7.7, 24.9 wk). Patients who failed FO 1.13 (IQR: 1.05, 1.21); P , 0.0001]; lower g-glutamyltransferase
therapy had a lower birth weight [1020 g (IQR: 737, 1776 g) [54 U/L (IQR: 41, 103 U/L) compared with 112 U/L (IQR: 76,
compared with 1608 g (IQR: 815, 2438 g); P = 0.03] and birth 168 U/L); P = 0.0002]; higher aspartate aminotransferase [200 U/L
length [36.2 cm (IQR: 32.0, 41.5 cm) compared with 42.0 cm (IQR: (IQR: 101, 354 U/L) compared with 115 U/L (IQR: 70, 174 U/L);
34.5, 47.0 cm); P = 0.05] and were older [20.4 wk (IQR: 9.9, P = 0.003] and alanine aminotransferase [131 U/L (IQR: 67,
38.6 wk) compared with 11.7 wk (IQR: 7.3, 21.4 wk); P = 0.02] 246 U/L) compared with 75 U/L (IQR: 38, 152 U/L); P = 0.03];
at FO therapy initiation than did patients whose cholestasis re-
solved. There was no statistically significant difference in gesta-
tional age or age at initiation of PN between patients who failed
FO therapy and those who responded.

Influence of baseline anthropometry


There was no statistically significant difference in weight-for-age
z score [21.41 (IQR: 22.80, 20.10) compared with 21.45 (IQR:
22.38, 20.60); P = 0.82] at the time of FO therapy initiation
between patients who failed therapy and those who responded
(Figure 2). Patients who failed FO therapy had a lower LAZ
[22.88 (IQR: 24.49, 21.64) compared with 21.85 (IQR: 22.85,
20.93); P = 0.05] and head circumference-for-age z score [22.17
(IQR: 23.51, 20.88) compared with 21.36 (IQR: 22.45, 20.40);
P = 0.06] at the time of FO therapy initiation than patients whose
cholestasis resolved. 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
Influence of baseline laboratory values are box-and-whisker plots, where each box represents the IQR, the horizon-
tal line represents the median, and the vertical whiskers extend #1.5 times
Cholestasis resolved in 96% (89/93) of patients with DB the IQR. P values are from Wilcoxon’s rank-sum tests. HCZ, head circumference-
2–4.9 mg/dL at FO initiation, 86% (49/57) with DB 5–9.9 mg/dL, for-age z score; LAZ, length-for-age z score; WAZ, weight-for-age z score.
PREDICTORS OF FISH-OIL THERAPY FAILURE 5 of 8

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) 2 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, g-glutamyltransferase; INR, international normalized ratio; PELD, pediatric end-stage liver disease.

and a higher PELD score [22 (IQR: 14, 25) compared with 12 diagnoses resulting in intestinal failure. Most patients (96%) un-
(IQR: 7, 15); P , 0.0001] (Figure 3). There was no statistically derwent $1 surgical procedure before FO initiation, and approxi-
significant difference in serum albumin at FO initiation between mately half (49%) had a stoma present at the time of FO initiation.
patients who failed FO therapy and those who responded [2.8 g/dL There were no differences in stoma presence or location at the time
(IQR: 2.5, 3.3 g/dL) compared with 3.1 g/dL (IQR: 2.6, 3.5 g/dL)]. of FO initiation between patients who failed FO therapy and those
whose cholestasis reversed (Table 3).
Forty-four percent of patients who failed parenteral FO therapy
Influence of baseline medical history had a history of gastrointestinal bleeding before FO initiation
Intestinal failure was caused by short bowel syndrome in 155 compared with 17% who did not fail therapy (P = 0.003). Patients
(85%) patients, motility disorder in 10 (5%), absorptive disorder in who failed FO therapy were more likely to be mechanically ven-
4 (2%), and miscellaneous other reasons in 13 (7%) (data not shown). tilated or septic at the time of FO initiation than patients who did
Gastroschisis was included as an etiology of short bowel syndrome, not fail [11 (42%) compared with 27 (18%), P = 0.007; 7 (29%)
although its morbidity is often caused by motility dysfunction. The compared with 9 (6%), P = 0.002] (Figure 4). There was no sta-
most common diagnosis resulting in intestinal failure was necrotizing tistically significant difference in vasopressor requirement at the
enterocolitis (43%). There were no statistically significant differ- time of FO initiation between patients who failed FO therapy and
ences between treatment failures and nonfailures with regard to the those who responded [2 (8%) compared with 5 (3%)].
6 of 8 NANDIVADA ET AL.

Nongastrointestinal comorbidities were more prevalent among disease (31, 32). Our study protocol at BCH requires initiating
patients who failed treatment than those whose cholestasis re- parenteral FO when DB is .2 mg/dL. However, at institutions
solved [21/26 (81%) compared with 83/156 (53%); P = 0.009]. without expertise managing IFALD or access to FO, the optimal
Patients who failed FO therapy were more likely to have a neu- time for transfer remains unclear. Although practitioners can
rologic [6 (23%) compared with 12 (8%); P = 0.03], genetic/ agree that transfer should be pursued before the onset of irre-
chromosomal [5 (19%) compared with 10 (6%); P = 0.04], versible liver disease, this point can be difficult to determine.
hematologic/oncologic [4 (15%) compared with 7 (4%); P = Furthermore, initiating FO therapy requires patients to be en-
0.05], or endocrinologic [5 (19%) compared with 4 (3%); P = rolled in a formal study with close long-term follow-up, placing
0.004] comorbidity present at FO initiation than patients who considerable demands on patients and families. It is therefore of
did not fail therapy (Supplemental Table 2). great importance to be able to accurately provide prognostic
information and to predict the likelihood of response to therapy.
However, there are currently no available data to our knowledge
Independent predictors of treatment failure to inform these difficult treatment decisions and to set expec-
A multivariate analysis revealed that a PELD score $15, history tations for providers and caregivers.
of gastrointestinal bleeding, age $16 wk, presence of non- In this study of 182 PN-dependent patients with IFALD treated
gastrointestinal comorbidities, and mechanical ventilation at with parenteral FO therapy, 86% experienced resolution of bio-
the time of FO initiation were independent predictors of treat- chemical cholestasis and 14% failed therapy, with a 4% transplant
ment failure (Table 1). No other effects, including normal birth rate and 10% mortality rate. Of the 18 IFALD-associated deaths, 8
weight ($2500 g), LAZ, and sepsis at the time of FO initiation, occurred after redirecting care for reasons unrelated to their liver
were independently predictive of treatment failure after adjusting disease. Patients who failed FO therapy were older and had more
for the aforementioned variables. advanced biochemical and clinical liver disease at the time of FO
initiation than patients who responded to therapy. FO initiation at
ages $16 wk, a PELD score $15, history of gastrointestinal
DISCUSSION bleeding, presence of nongastrointestinal comorbidities, and me-
Long-term PN is lifesaving for patients with intestinal failure chanical ventilation at the time of FO initiation were independent
but is associated with potentially serious complications, including predictors of treatment failure.
IFALD. Historically, the only effective treatment options for Other reports of treatment with FO monotherapy have reported
IFALD have been the discontinuation of PN, lipid reduction, and transplant rates of 0–10% and mortality rates of 0–25% (9–13,
liver transplantation (23–26). The introduction of parenteral FO 33, 34). The largest of these reports included a cohort of 97
therapy has changed the way IFALD is managed, allowing most patients with IFALD and reported resolution of cholestasis in
treated children to experience resolution of cholestasis and avoid 86% of patients, no transplants, and death in 14% of patients
progression to end-stage liver disease (13). However, FO therapy (13). That study reported a mortality rate of 35% with a baseline
is not broadly available in the United States because it is not DB .10 mg/dL compared with 6% with an initial DB ,5 mg/dL;
approved by the Food and Drug Administration and must be however, it excluded patients who had a congenital diagnosis with
given under a compassionate-use policy at approved institutions a lethal prognosis. Although patients were not excluded based
(27). For this reason, there is a need for establishing recom- on comorbidities, this is consistent with our treatment failure rate
mendations for practitioners at institutions without access to FO (transplant plus mortality) of 44% in patients with DB $10 mg/dL
therapy to guide transfer decisions. at FO initiation and 4% in patients with DB ,5 mg/dL at FO
Risk factors for the development of IFALD have been de- initiation.
scribed (28–30), and patients with DB .5.8 mg/dL have been Most patients who failed FO therapy for the treatment of IFALD
reported to be at a greater risk for progression to end-stage liver were severely ill, both acutely and chronically, as a result of and
oftentimes unrelated to their liver disease at the time at which
FO was started. However, despite this, many severely ill patients
with substantial laboratory derangements and comorbidities were
still able to achieve resolution of biochemical cholestasis with
FO therapy, suggesting that practitioners and caregivers may be
cautiously optimistic that a treatment response is possible. Of the
patients whose cholestasis resolved, 24% had a PELD score $15
at the time of FO initiation (Table 1), and 17% had a history of
gastrointestinal bleeding. Cholestasis resolved in 56% of patients
with DB $10 mg/dL at FO initiation and in 45% of those with
a baseline DB $15 mg/dL. These results suggest that the re-
versibility of IFALD cannot be reliably determined and support
the practice of offering FO therapy to all PN-dependent patients
with IFALD, even those with a markedly elevated bilirubin and
PELD score.
FIGURE 4 Severity of illness at FO initiation. Sample sizes for chole- Septic episodes have been shown to contribute to the development
stasis resolved and treatment failures, respectively, were n = 147 and n = 26
for the percentage of patients who were mechanically ventilated, n = 149 and
of IFALD (35, 36). However, the presence of sepsis at the time of FO
n = 25 for those requiring vasopressors, and n = 145 and n = 24 for those who initiation did not predict treatment failure. Sepsis was the most
were septic at the time of FO treatment initiation. FO, fish oil. common cause of death in patients whose cholestasis never resolved
PREDICTORS OF FISH-OIL THERAPY FAILURE 7 of 8
and those whose cholestasis successfully resolved with FO therapy license agreement for the use of Omegaven has been signed by BCH and
but subsequently died. Three patients who died of sepsis after Fresenius Kabi, and a patent has been submitted by BCH on behalf of KMG
resolution of cholestasis were not deemed treatment failures despite and MP. None of the other authors reported a conflict of interest related to
the study.
the inability to prove that these patients’ sepsis was completely
unrelated to liver disease. The sources of their infections were
multiple enterocutaneous fistulae and recurrent intra-abdominal
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