Journal of Parenteral and Enteral

Nutrition
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Incidence, Prevention, and Treatment of Parenteral NutritionAssociated Cholestasis and Intestinal

Failure Associated Liver Disease in Infants and Children: A Systematic Review

Giuseppe Lauriti, Augusto Zani, Roberto Aufieri, Mara Cananzi, Pierluigi Lelli Chiesa, Simon Eaton and Agostino Pierro
JPEN J Parenter Enteral Nutr published online 26 July 2013
DOI: 10.1177/0148607113496280
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496280

research-article2013

PENXXX10.1177/0148607113496280Journal of Parenteral and Enteral NutritionLauriti et al

Article

Incidence, Prevention, and Treatment of Parenteral

NutritionAssociated Cholestasis and Intestinal Failure
Associated Liver Disease in Infants and Children: A
Systematic Review

Journal of Parenteral and Enteral

Nutrition
Volume XX Number X
Month 2013 116
2013 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0148607113496280
jpen.sagepub.com
hosted at
online.sagepub.com

Giuseppe Lauriti, MD, PhD1,2; Augusto Zani, MD, PhD1; Roberto Aufieri, MD1;
Mara Cananzi, MD, PhD1; Pierluigi Lelli Chiesa, MD2; Simon Eaton, BSc, PhD1;
and Agostino Pierro, MD, FRCS(Eng), FRCS(Ed), FAAP3

Abstract
Background: Cholestasis is a significant life-threatening complication in children on parenteral nutrition (PN). Strategies to prevent/
treat PN-associated cholestasis (PNAC) and intestinal failureassociated liver disease (IFALD) have reached moderate success with little
supporting evidence. Aims of this systematic review were (1) to determine the incidence of PNAC/IFALD in children receiving PN for
14 days and (2) to review the efficacy of measures to prevent/treat PNAC/IFALD. Methods: Of 4696 abstracts screened, 406 relevant
articles were reviewed, and studies on children with PN 14 days and cholestasis (conjugated bilirubin 2 mg/dL) were included.
Analyzed parameters were (1) PNAC/IFALD incidence by decade and by PN length and (2) PNAC/IFALD prevention and treatment
(prospective studies). Results: Twenty-three articles (3280 patients) showed an incidence of 28.2% and 49.8% of PNAC and IFALD,
respectively, with no evident alteration over the last decades. The incidence of PNAC was directly proportional to the length of PN (from
15.7% for PN 1 month up to 60.9% for PN 2 months; P < .0001). Ten studies on PNAC met inclusion criteria. High or intermediatedose of oral erythromycin and aminoacid-free PN with enteral whey protein gained significant benefits in preterm neonates (P < .05, P =
.003, and P < .001, respectively). None of the studies reviewed met inclusion criteria for treatment. Conclusions: The incidence of PNAC/
IFALD in children has no obvious decrease over time. PNAC is directly correlated to the length of PN. Erythromycin and aminoacidfree PN with enteral whey protein have shown to prevent PNAC in preterm neonates. There is a lack of high-quality prospective studies,
especially on IFALD. (JPEN J Parenter Enteral Nutr. XXXX;XX:XX-XX)

Keywords
parenteral nutrition; intestinal failure; cholestasis; liver disease; child

Background
Parenteral nutrition (PN) provides life-saving artificial nutrition and adequate growth in infants with insufficient intestinal
function due to prematurity and/or major abdominal gastrointestinal surgical procedures. Moreover, PN is especially
required in infants and children with intestinal failure (IF)
caused by a reduced absorptive surface (eg, short bowel syndrome); an intact, although inefficient, mucosal surface (eg,
congenital enterocyte disorders); or an intact mucosal surface
with extensive motility dysfunction (eg, chronic intestinal
pseudo-obstructions).1
However, patients on prolonged PN are at risk for a spectrum of PN-associated hepatobiliary disorders, ranging from
cholestasis to end-stage liver disease.2 Since its observation in
early 1970s,3-5 PN-associated cholestasis (PNAC) has more
often been found in preterm neonates and infants, as it occurs
earlier and hepatic dysfunction can rapidly progress in these
patients, therefore remaining one of the most significant complications of prolonged PN.8 Furthermore, infants and children

with IF are at risk for IF-associated liver disease (IFALD), the

most relevant and persistent complication in pediatric IF

From 1Department of Surgery, UCL Institute of Child Health, London,

UK; 2Department of Paediatric Surgery, G. dAnnunzio University,
Chieti-Pescara, Italy; and 3Division of General and Thoracic Surgery,
Hospital for Sick Children, Toronto, Canada.
Financial disclosures: The study was partly supported by grants from
the Mittal Research Foundation, London, UK. Agostino Pierro and
Simon Eaton have been consultants for the development of novel
parenteral amino acids mixtures and have consequently received financial
contributions from Fresenius-Kabi.
Received for publication April 23, 2013; accepted for publication June
12, 2013.
Corresponding Author:
Agostino Pierro, MD, FRCS(Eng), FRCS(Ed), FAAP, Hospital for
Sick Children, 555 University Ave, Suite 1526First Floor Hill Wing,
Toronto, ON M5G 1X8, Canada.
Email: agostino.pierro@sickkids.ca.

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Journal of Parenteral and Enteral Nutrition XX(X)

requiring long-term PN and the most consistent negative prognostic indicator for their overall survival.1,7
Nonetheless, despite advances in the knowledge of bile formation physiology8 and of the molecular basis for neonatal
cholestasis,9 both PNAC and IFALD are not completely elucidated consequences of PN therapy in infants. A multifactorial
etiology has been proposed implicating low birth weight, prematurity, enzyme deficiencies, genetic causes, anatomic factors, susceptibility to cholestatic injury, and factors relevant to
the PN itself.2,7,9-12 A further risk factor is the occurrence of
severe infections, due to the requirement for central line for
infusion of PN, and bacterial overgrowth caused by enteral
starvation and immature immune function.13
The prevalence of PNAC and IFALD varies considerably
among studies, but it is estimated to be approximately 40%60% in infants and up to 85% in neonates who are receiving
long-term PN for IF. Furthermore, the prevalence of the IFALD
is unknown because there is no established definition of liver
disease in this setting and it is unclear whether IFALD should
be diagnosed on the basis of clinical, biological, or histological
criteria.1
Some children who receive long-term PN eventually
develop end-stage liver disease. Although their proportion was
15% in the 1990s,2 a more recent study suggests that careful
management may reduce this to 3%.14 End stage liver disease
has a mortality rate approaching 100% within a year of diagnosis if they are unable to be weaned off PN or fail to receive a
liver and/or intestinal transplant.15,16 Furthermore, small bowel
transplantation is limited by a shortage of organ donors, especially for premature infants, and by 10 years, patient and intestine survival rate is 46% and 29% for intestine-only recipients,
and 42% and 39% for combined liver-intestine, respectively.17
Several enhancements in prolonged PN were achieved
throughout last decades, such as improvements in PN components and intensive care measures. Aseptic placement techniques and strict catheter care have reduced sepsis related to
central line catheter.18 Moreover, no significant differences
were noticed in the incidence of catheter related-bloodstream
infections in multiple lumen vs single lumen catheters.19,20
However, there remains a risk of septicaemia that could be due
to bacterial translocation.21
In spite of these improvements, preventive strategies for
both PNAC and IFALD are limited and have reached moderate
success, and current therapies for these diseases have little supporting evidence in infants.7,22 Even if the most effective treatment is advancement to full enteral feeds and discontinuation
of PN, this process is often impossible because of poor intestinal function or inadequate gut length.23 Therefore, PNAC and
IFALD remain significant life-threatening complications and 1
of the recognized predictor factors of mortality in infants and
children on long-term PN.22
Currently, no systematic reviews are available on incidence
of both PNAC and IFALD in infants and children. An exhaustive review summarizes current knowledge on PNAC, with

meticulous considerations in the prevention and treatment of

this disease.24 However, neither a systematic review on studies
included was done nor a precise definition of PNAC was mentioned by authors. A recent study systematically reviewed the
potential benefits and harms of -3 fatty acid lipid emulsions
to prevent complications associated with PN.25 However, the
authors included articles with nonhomogeneous characteristic,
such as different initial conditions of patients (eg, prematurity,
patient with IF, and infants with congenital heart disease), different quality of the studies (eg, randomized controlled trial,
RCT, and cohort studies with historical controls), and nonuniform definition of PNAC and IFALD. Furthermore, an article
by Barclay et al26 reviewed interventions in pediatric IF and its
complications (sepsis and IFALD). Although their systematic
review did include measures taken to prevent or treat cholestasis, authors did not mention any definition of IFALD, consequently not all the studies included were strictly related to this
disease.
Hence, the aims of our systematic review were (1) to determine if the incidence of PNAC and IFALD have changed over
time among infants and children receiving PN for 14 days
and if there is a correlation between PNAC, IFALD, and length
of PN; and (2) to evaluate possible methods of prevention and
treatment of PNAC and IFALD.

Materials and Methods

Search Strategy
A systematic review of the Literature using defined search criteria was performed (Figure 1). Studies published between
1950 and March 2013, using Medline, Embase, and the
Cochrane Library were searched. The following search terms
were used: infant or child or baby or paediatric or
pediatric or neonate and parenteral and liver or
hepatic or hepatitis or cholestasis or bilirubin. The
explode function and the truncation terms $ and * were
used as appropriate to each database to search for all possible
variations of the keywords. This search strategy yielded 4696
articles. These 4696 titles and abstracts were screened independently by 2 authors (GL and RA): Articles not relevant to
PNAC or IFALD in infants and children were excluded. Of all
potentially relevant abstracts, 406 full-text articles were
reviewed for the different inclusion criteria. In addition, the
same 2 authors screened the references of all full-text articles
to identify publications not retrieved by the electronic searches.
For individual selected studies 2 authors (GL and AZ) independently graded the level of evidence (LoE) presented using the
Oxford Centre for Evidence-Based Medicine Levels of
Evidence methodology (Table 1).27
To obtain homogeneous collection of patients, included
articles were divided into 3 groups according to pediatric age
or liver disease both in incidence, prevention, and treatment
analysis (Table 2).

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Lauriti et al

3
Table 2. Subgroups of Studies According to Pediatric Age or
Liver Disease.
Group
1
2

Definition
Studies including exclusively preterm neonates (ELBW
and VLBW), focusing on PNAC
Studies on neonates (LBW, at term, or not specified),
infants, and children without IF related disease,
focusing on PNAC;
Studies on neonates, infants, and children with IF
entirely focusing on IFALD

ELBW, extremely low birth weight; IF, intestinal failure; IFALD, intestinal failureassociated liver disease; LBW, low birth weight; PNAC, parenteral nutritionassociated cholestasis; VLBW, very low birth weight.

Figure 1. Search criteria applied to perform the systematic

review of the literature.
Table 1. The Oxford Centre for Evidence-Based Medicine
Levels of Evidence Methodology.27
LoE
1a
1b
1c
2a
2b
2c
3a
3b
4
5

Prevention or Therapy Study Type

SR (with homogeneity) of RCTs
Individual RCT (with narrow confidence interval)
All or nonea
SR (with homogeneity) of cohort studies
Individual cohort study (including low quality RCT)
Outcomes research; ecological studies
SR (with homogeneity) of case-control studies
Individual case-control study
Case-series (and poor quality cohort and case-control
studies)
Expert opinion without explicit critical appraisal, or based
on physiology, bench research or first principles

LoE, level of evidence; RCT, randomized controlled trial; SR, systematic

review.
a
All patients died before the medical prescription became available, but
some now survive on it; or when some patients died before the medical
prescription became available, but none now die on it.

Incidence of PNAC and IFALD, their prevention, and their

treatment were analyzed (Figure 2). The inclusion criteria for
these parameters are reported below.

review only studies where cholestasis or liver disease were

defined as conjugated bilirubin (CB) 2 mg/dL (or 34 mol/L)
in association with a prolonged duration of PN administration
( 14 days, Figure 2), as most episodes of PNAC or IFALD
occur after 2 weeks of PN.2,28,29 Furthermore, we chose CB as a
marker for both PNAC and IFALD as it is the most frequently
used measure in studies of PNAC/IFALD and is clearly related
to the risk of liver failure.6,9-12,15,16,18 In addition, to avoid any
synonymous use of PNAC and IFALD, only articles with an
explicit mention of IF were included in the IFALD group.
Patients developing cholestasis for causes unrelated to PN
(eg, genetic or metabolic disorders, congenital infections, haemolysis, liver dysfunction, or extrahepatic obstructions) were
excluded from the study. Case reports and case series were
excluded: Only articles with 10 patients were considered in
our systematic review. Patients older than 18 years were not
included.

Prevention
To gain stronger evidence for preventative, only prospective
RCT or cohort studies on prevention of PNAC and IFALD in
infants and children (age < 18 years) were included (LoE 1 and
2, Table 1). Patients had to receive PN for 14 days, and not to
have been affected by cholestasis or liver disease (ie, CB had
to be < 2 mg/dL) at the beginning of studies (Figure 2).

Treatment
Similar to inclusion criteria for prevention, only prospective
RCT or cohort studies on treatment of in infants and children
(age < 18 years) were included (LoE 1 and 2). PNAC and
IFALD were defined as CB 2 mg/dL with PN 14 days
(Figure 2).

Data Analysis

Incidence
In spite of different definitions of PNAC and IFALD and to gain
less biases, we determined to include in the present systematic

Incidence of cholestasis per decades (from 1970s to 2000s) and

per length of PN were assessed by chi-square test for trend.
Results showing P < .05 were considered significant. If

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Journal of Parenteral and Enteral Nutrition XX(X)

Figure 2. Inclusion criteria established to determine incidence, prevention, and treatment of parenteral nutritionassociated cholestasis.
CB, conjugated bilirubin; PN, parenteral nutrition.

methodologically feasible, studies on prevention or treatment

were further compared by meta-analysis software (Review
Manager, RevMan version 5.2, Nordic Cochrane Centre,
Cochrane Collaboration 2012, Copenhagen, Denmark).

Results
Incidence
Twenty-three articles (3280 patients) met the inclusion criteria
(Tables 3a and 3b).10,11,12,15,28-46 However, 1 study15 reported
only the median (with interquartile range, IQR) duration of
PN.
The overall incidence of cholestasis coming from all
included studies was 29.9%, considering both PNAC and
IFALD. Looking at PNAC, the incidence of cholestasis was
28.2% and, respectively, 25.5% in preterm neonates (Group 1),
and 30.6% in neonates at term or not specified, infants, and
children (Group 2; Table 3a). The incidence of IFALD was
49.8% in pediatric patients with IF (Group 3; Table 3b).
To reduce biases given by not specified subgroups of preterm neonates and different durations of PN, we further analyzed the studies of Group 2 in relation to the length of PN.
Five of the 14 articles included in Group 210,11,37-39 analyzed
the relationship between the duration of PN and PNAC (Table
4). When possible, patients overlapping with Group 1 (ELBW
and VLBW) were excluded. The incidence of PNAC was

directly proportional to the length of PN, with an incidence

varying from 15.7% in patients receiving PN for 14-30 days up
to 60.8% in patients receiving PN for >60 days (Figure 3; P <
.0001).
Furthermore, to examine the incidence of PNAC/IFALD
throughout the past 4 decades we considered only those studies10-12,15,30-32,34-40,44-46 with a precise study period mentioned
(Tables 3a and 3b, Figure 4a). Because of the paucity of studies
included in both Groups 1 and 3, it seemed no achievable to
determine any variation throughout past decades in these subgroups of patients. There appeared to be an alteration in the
incidence of PNAC over time in the Group 2,10,11,34-40 although
it was not possible to compare these data due to the overlapping periods that the studies were conducted over (Figure 4b).
Similarly, to reduce bias resulting from including studies that
were conducted over a long period (with underlying improvement on PN during the study), we examined the incidence of
PNAC in only those studies with a study period 5
years.10,11,34,36-38,40 Again, there was no obvious alteration in the
incidence of PNAC over time (Figure 4c).

Prevention
Ten studies met the inclusion criteria for prevention of the disease (Table 5).30,33,43,47-53 None of these articles were related to
IFALD. The articles included investigated possible maneuvers
to reduce the incidence of PNAC throughout choleretic

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Lauriti et al

Table 3a. Studies on the Incidence of Parenteral NutritionAssociated Cholestasis (PNAC) in Neonates, Infants, and Children
According to Study Period.
N

Reference

Days of PN

CB

PNAC pts

PNAC
Incidence (%)

Prematurity

14

2 mg/dL

0/22

Prematurity
Prematurity

21
14

2 mg/dL
2 mg/dL

38/103
55/445

37
12.3

Prematurity

14

2 mg/dL

179/723

24.7

Prematurity, NEC
Prematurity

14
>21

2 mg/dL
>3 mg/dL

87/127
7/12

68.5
58

Surgery

14

2 mg/dL

8/19

42.1

n.m.
Prematurity,
surgery, RDS
n.m.
Surgery
Prematurity,
surgery, sepsis,
ECMO
n.m.
n.m.
Gastroschisis
Prematurity,
surgery, ECMO
Surgical
gastrointestinal
condition
n.m.

14
14

2 mg/dL
2 mg/dL

44/77
11/33

57
33.3

14
28
14

2 mg/dL
>2.35 mg/dL
2 mg/dL

22/72
27/74
15/70

31
36.5
21.4

14
21
21
14

2 mg/dL
2 mg/dL
2 mg/dL
2 mg/dL

31/124
24/141
16/71
178/643

25
17
22.5
27.7

21

2 mg/dL

14/32

43.8

>15

2 mg/dL

6/55

10.9

>14

>2.35 mg/dL

9/53

17

>49

2 mg/dL

17/32

Study Period

Age of Ptsa

Indication for PN

ELBW,
VLBW
ELBW
ELBW,
VLBW
ELBW,
VLBW,
LBW
VLBW
VLBW

Group 1b
1

Slagle TA et al30

1985-1986

2
3

Baserga MC et al31
Costa S et al12

1998-2000
1996-2006

Christensen RD
et al11

2002-2006

5
-

Duro D et al32
Brown MR et al33

2004-2007
n.m.

Touloukian RJ
et al34
Kubota A et al35
Vileisis RA et al36

1972-1974
1971-1982
1977-1978

Neonates,
infants
Neonates
Neonates

9
10
11

Kubota A et al35
Beath SV et al37
Forchielli ML
et al38

1983-1987
1988-1992
1990

Neonates
Neonates
Infants

12
13
14
15

1992-1996
1997-1999
1996-2007
2002-2006

16

Kubota A et al35
Wright K et al10
Jensen AR et al39
Christensen RD
et al11
Nehra D et al40

Neonates
Neonates
Neonates
LBW,
neonates
Neonates

Farrell MK et al41

n.m.

Puntis JWL et al42

n.m.

Infants,
children
Neonates

Drongowski RA
et al29
Teitelbaum DH
et al28
Fok TF et al43

n.m.

Neonates

Prematurity, NEC,
PDA, surgery,
abdominal
distension
n.m.

n.m.

Neonates

n.m.

>14

2 mg/dL

9/21

n.m.

Neonates

Prematurity, feed
intolerance,
sepsis, NEC,
surgery, others

>14

>2.94 mg/dL

58/78

Group 2b
6
7
8

2007-2011

53.1
43
74.4

CB, conjugated bilirubin (expressed in mg/dL); ECMO, extracorporeal membrane oxygenation; ELBW, extremely low birth weight; LBW, low birth
weight; N, numbers of references to be related to Figure 3a (in articles with mentioned study period); NEC, necrotizing enterocolitis; n.m., not mentioned; PDA, patent ductus arteriosus; PN, parenteral nutrition; PNAC: parenteral nutritionassociated cholestasis; RDS, respiratory distress syndrome;
VLBW, very low birth weight.
a
Age of patients at the beginning of PN.
b
Group refers to Table 2.

agents,47,48 antibiotic therapy,49-51 and improvement in nutrition

intake, enhancing components of PN, such as protein, trace
elements, or lipids,43,53 and supporting enteral nutrition30,33 or
PN cycling.52

Choleretic agents.Trying to improve intrahepatic and

extrahepatic bile flow and biliary sludge, Teitelbaum et al47
evaluated the effects of cholecystokinin (CCK, 0.04 g/kg per
dose, i.v., every 12 hours for 14 days) on the development of

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Journal of Parenteral and Enteral Nutrition XX(X)

Table 3b. Studies on the Incidence of Intestinal FailureAssociated Liver Disease (IFALD) in Pediatric Population (Group 3, see Table
2) According to Study Period.
N

Reference

Study Period

Age of Ptsa

Indication for PN

Days of PN

CB

IFALD
Pts

IFALD
Incidence (%)

Group 3: Neonates, infants, and children with IF

17
18
19
20

Quirs-Tejeira RE
et al44
Sondheimer JM
et al45
Wales PW et al15
Kglmeier J et al46

1975-2000

Infants, children

SBS

>90

2 mg/dL

18/78

23

1984-1997

Infants

Surgery

90

2 mg/dL

28/42

67

1997-2001
2001-2002

Neonates
Infants, children

SBS
Prematurity,
surgery, oncology

Median 86ddb
>28

>2.94 mg/dL
2.94 mg/dL

25/40
55/93

62.5
59.1

CB, conjugated bilirubin (expressed in mg/dL); N, numbers of references to be related to Figure 3a; PN, parenteral nutrition; SBS, short bowel syndrome.
Age of patients at the beginning of PN.
b
PNAC reported after a median of 86 days of PN (interquartile range, IQR, 55-138 days).
a

Table 4. Relation Between the Incidence of Parenteral NutritionAssociated Cholestasis (PNAC) and Duration of Parenteral Nutrition
(PN) Related to Group 2 (see Table 2).
Reference
Forchielli ML et al38
Forchielli ML et al38
Christensen RD et al11
Wright K et al10
Forchielli ML et al38
Jensen AR et al39
Beath SV et al37

Forchielli ML et al38
Christensen RD et al11
Wright K et al10
Forchielli ML et al38
Jensen AR et al39

Wright K et al10
Christensen RD et al11
Forchielli ML et al38
Wright K et al10
Christensen RD et al11
Wright K et al10

Days of PN
Duration of PN 14-30 days
14
15-21
14-28
14-30
22-28
25
28
Duration of PN 30-60 days
29-42
29-56
31-60
43-56
50
Duration of PN > 60 days
61-90
57-100
>56
91-120
>100
121-150

severe PNACdefined as CB levels of 5.0 mg/dLin a

neonatal population. CCK failed to prevent severe PNAC
(Table 5). The study was a RCT recruiting initially only
severely premature infants (< 1000 g at birth and with an estimated gestational age of < 28 weeks, Group 1) and afterward
also surgical neonates (< 30 days of age at the time of enrolment, Group 2). Therefore, we assigned to this study a LoE 2b.
The prospective study by Heubi et al48 investigated the
prophylactic effect of tauroursodeoxycholic acid (TUDCA,
30 mg/kg/day) in the development of PNAC. As shown in
Table 5, TUDCA failed to show any effect in preventing
PNAC. Because of difficulties in enrolment, authors proceed

PNAC Pts
0/9
0/19
55/365
5/123
2/6
16/71
27/74
2/8
38/77
10/68
0/5
35/71
5/14
12/17
9/14
3/4
1/1
1/1

PNAC Incidence (%)

0
0
15
4.1
33.3
22.5
36.5

25
46
14.7
0
49

35.7
71
64.3
75
100
100

with an open-label trial with comparison of concurrently

untreated controls who refused participation. The population
included in the study was heterogeneous, including ELBW
and VLBW on one hand (Group 1), but also neonates with a
birth weight > 1500 g (Group 2). Furthermore, some of the
infants treated with TUDCA had been submitted to wide
intestinal resection. Therefore, results regarding the effects of
TUDCA should be interpreted with caution in infants with
short bowel syndrome, since the length of remnant ileum is
essential to ensure bile acid absorption and thus, possible
effect of TUDCA in such condition. For these reasons, the
article was rated at LoE 2b.

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Lauriti et al

7
any methods of randomization. The study was then rated at
LoE 1b. The meta-analysis on these 2 RCTs (Figure 5) demonstrated a significant beneficial effect of erythromycin in preventing PNAC (P < .001).
Kubota et al51 explored the preventive effect on PNAC of 2
different concentrations of metronidazole (MNZ, 25 and 50
mg/kg/day) in a surgical neonatal population (Group 2). The
development of PNAC was not reduced by the administration
of MNZ at each concentration (Table 5). Because of the small
number of patients enrolled and the comparison between not
concurrently cases and controls, the study was allocated a LoE
2b. As a result of the low LoE of the study, meta-analysis of
this article was not achievable.

Figure 3. Incidence of parenteral nutritionassociated

cholestasis (PNAC) was directly proportional to the length of
parenteral nutrition (PN) in Group 2, assessed by chi-square test
for trend: P < .0001. Data are expressed as means.

Antibiotic therapy. With regard to antibiotic treatment, 2 different RCTs49,50 focused on the possible prevention of PNAC
with erythromycin in VLBW neonates (Group 1). In the first
one,49 high-dose of oral erythromycin (12.5 mg/kg/dose every
6 hours for 14 days) significantly lowered the incidence of
PNAC in treated neonates (18/91, 20%) in comparison with
controls (37/91, 41%; P = .003, Table 5). Moreover treated
infants achieved full enteral nutrition significantly earlier (P <
.001), the duration of PN was significantly decreased by 10
days (P < .001), and fewer infants receiving erythromycin had
2 or more episodes of septicaemia compared with placebo
patients (P = .03). The RCT was well-constructed, with possible low confounding bias given by his duration. It was conducted in 2 phases, during 2 periods, resulting in an overall
length of approximately 8 years. Even if all VLBW infants
were routinely started on the same PN, we could not assume
the nonexistence of any further benefit coming from any sort of
up-to-date protocols or therapies in such long time. However,
the article was rated at LoE 1b. In the second RCT50 intermediate-dose of oral erythromycin (5 mg/kg/dose every 6 hours for
14 days) significantly lowered the incidence of PNAC in
treated neonates (2/19, 10.5%) in comparison with controls
(10/26, 38.5%; P < .05, Table 5). Moreover, the number of
days required to achieve full enteral feeding (P = .01), the
duration of PN (P < .05), and the time required to achieve a
body weight 2500 g (P < .05) were significantly shorter in
treated infants. Furthermore, the incidence of necrotizing
enterocolitis (NEC) stage IIa after 14 days of treatment was
significantly lower in the erythromycin group (P < .05). The
RCT was well-constructed, with adequate power calculation of
the sample size, and without significant confounding bias
within cases and controls, even if the authors did not mention

Nutrition intake. To reduce the incidence of PNAC, in an RCT

by Brown et al33 on VLBW infants (Group 1), the treatment
group received aminoacid-free PN and whey protein enterally
with added premature infant formula, whereas controls
received standard PN with amino acids and enteral premature
formula. After up to 3 weeks of PN, none of whey group infants
developed PNAC (0/17, 0%), while 7/12 (58%) controls had
PNAC (P < .001; Table 5). The RCT showed some weak point,
as the authors did not mention any methods of randomization
or describe the use of power calculations that lead to the numbers recruited and did not state about concurrent administration
of further treatments. Moreover, the number of patients
recruited was too undersized. These possible risks of confounding biases lead this study to be assigned a LoE 2b.
Similarly, Slagle et al30 evaluated the potential benefit of
early low-volume feedings in very low birth weight (VLBW)
neonates in an RCT (Table 5). Although neither early-feeding
infants nor delayed feeding patients developed PNAC, the
mean serum concentrations of CB for VLBW in the early feeding group were slightly lower than those in the delayed feeding
group on day 18 (0.2 0.02 mg/dl vs 0.3 0.05 mg/dl) and day
29 of life (0.2 0.02 mg/dl vs 0.3 0.05 mg/dl, P < .05; data
expressed mean SEM). Leaving aside the lack of methodology used for the power calculation, the modest number of
patients recruited, and the epoch of the study, what it might be
surprising is that delayed feeding group did not demonstrate
any rising in CB after 15 days of total PN (0.3 0.03 mg/dl vs
0.3 0.05 mg/dl). Moreover, PN was initiated in all patients on
day 3 of life and was increased uniformly over 4 days (until
randomization to total PN or early oral feeding), so that we do
not have any data about alimentation on day 1 and 2 of life, as
well as further concurrent feeding from day 3 to day 7. The
article was then rated at LoE 2b.
Salvador et al52 compared the incidence of PNAC in VLBW
infants receiving cycle PN (amino acid solution, TrophAmine,
B. Braun Medical, Irvine, CA, over a 20-hour period, a soybean-based lipid emulsion, Intralipid 20%, Fresenius Kabi,
Homburg, Germany, over 18 hours, and dextrose over 24
hours) and those receiving continuous PN (TrophAmine over a
24-hour period, Intralipid 20% over 18 hours, and dextrose

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Journal of Parenteral and Enteral Nutrition XX(X)

Figure 4. (a) Included studies on incidence of parenteral nutritionassociated cholestasis (PNAC) or intestinal failureassociated
liver disease (IFALD) with a study period mentioned. *References are related to Tables 3a and 3b. (b) Incidence of PNAC ( 95%
confidential interval) in article with a study period mentioned. (c) Incidence of PNAC ( 95% confidential interval) in article with study
periods 5 years. (a, b, c) Dots express the average year of study period. Sizes of dots are related to number of patients in the study; see
legend. Horizontal lines delineate the corespective study period. (b, c) Test for trend not possible because of the overlapping periods
that the studies were conducted over.

over 24 hours). However, the incidence of PNAC was similar

in the 2 groups (32% and 31%, respectively; P = ns; Table 5).
The RCT was well-constructed, with adequate methods of randomization, without significant confounding bias within cases
and controls, even if no power calculation of the sample size
has been mentioned. The study was then rated at LoE 1b.
To enhance components of PN, Vileisis et al53 compared in a
RCT the hepatic effects of 2 different parenteral protein intakes,
a lower protein regimen (LP: 2.3 g/kg/day) and a higher protein
regimen (HP: 3.6 g/kg/day) in patients with structural gastrointestinal defect, NEC, and extreme prematurity with RDS
(Groups 1 and 2; Table 5). Although the incidence of PNAC in
the LP and HP groups were very similar (27% and 33%, respectively; P = ns), infants randomized to the HP group developed
PNAC earlier than the LP group (27 4 vs 47 6 days; P <
.01), and achieved a significantly greater peak of CB (8.4 1.6
vs 3.2 0.3 mg/dl; P < .001; data expressed mean SEM).
Leaving out the time of the study, the inclusion criteria to recruit
patients were indefinite, as authors did not mention further
information on the structural gastrointestinal defect, such as on

subsequent surgical procedures, thus omitting potential wide

intestinal resection. Furthermore, even if authors included
extreme prematurity neonates with RDS, birth weights were 2.4
0.2 kg in LP and 2.7 0.2 kg in HP, with gestational ages of
36.0 0.8 and 37.7 0.9 weeks, respectively, thus likely reducing the numbers of ELBW and VLBW neonates recruited. The
article was rated at LoE 2b.
Fok et al43 randomized preterm and at term neonates (Group
2) to receive either 1 or 0.0182 mmol/kg/d of manganese supplementation in a high-quality RCT (Table 5). Although there
was no significant difference in the occurrence of PNAC (58/78
vs 49/82; P = .073), significantly more infants in the high manganese group developed severe conjugated hyper-bilirubinaemia,
with peak serum CB > 100 mmol/L (5.9 mg/dL) in 32/78
patients vs 20/82; P = .038. The RCT illustrated well-constructed
methods, even if there were some low risk biases in the high
manganese group, such as slightly smaller gestational age (31.0
3.9 vs 32.0 4.8, respectively; mean SD), higher number of
neonates with NEC (42.3 vs 34.1%), lower days of age when PN
started (5.0 {4.0, 7.0} vs 5.0 {4.0, 8.0}), and more days on PN

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Lauriti et al

Table 5. Studies on Prevention of Parenteral NutritionAssociated Cholestasis (PNAC) in Children.

PNAC in Untreated
Pts (incidence %) P Value

Treatment

Choleretic agents
Teitelbaum DH et al47

1,2

RCT (2b)

10/114 (9)

13/111 (12)

ns

Heubi JE et al48

1,2

Cholecystokinin (0.04
g/kg/12 hours)
Tauroursodeoxycholic
acid (30 mg/kg/day)

Prospective
nonrandomized (2b)

22/22 (100)

32/32 (100)

ns

Erythromycin (12.5
mg/
kg/6 hours)
Erythromycin (5 mg/
kg/6 hours)
Metronidazole (25 mg/
kg/day)
Metronidazole (50 mg/
kg/day)

RCT (1b)

18/91 (20)

37/91 (41)

.003

RCT (1b)

2/19 (10.5)

10/26 (38.5)

<.05

Prospective
nonrandomized (2b)
Prospective
nonrandomized (2b)

2/9 (22)

4/21 (19)

ns

1/12 (8)

4/21 (19)

ns

RCT (2b)

0/17 (0)

7/12 (58)

<.001

RCT (2b)

0/18 (0)

0/22 (0)

ns

RCT (1b)
RCT (2b)

11/34 (32)
6/22 (27.3)

11/36 (31)
7/21 (33.3)

ns
ns

RCT (2b)

58/78 (74.4)

49/82 (59.8)

ns

Antibiotics
Ng PC et al49

Ng YY et al50

Kubota A et al51

Kubota A et al51

Nutrition intake
Brown MR et al33

Slagle TA et al30

Salvador A et al52
Vileisis RA et al53
Fok TF et al43

1
1,2

Aminoacid-free PN
with enteral bovine
whey protein
Early low-volume
enteral feeding
Early PN cycling
Low (2.5 g/kg/day) vs
high protein regimen
(4.0 g/kg/day)
Manganese
supplementation

Study Design (ratingb)

PNAC in Treated
Pts (incidence %)

Groupa

Reference

ns, not significant; PN, parenteral nutrition; PNAC, parenteral nutritionassociated cholestasis; RCT, randomized controlled trial.
a
Group refers to Table 2.
b
Rating refers to the Oxford Centre for Evidence-Based Medicine levels of evidence methodology28 (Table 1).

Figure 5. Meta-analysis on 2 different doses of erythromycin to prevent parenteral nutritionassociated cholestasis (PNAC). Ery,
erythromycin; QDS, quater die sumendus, 4 times a day.

(41.0 {26.0, 77.3} vs 40.0 {20.5, 67.5}; median {25th and 75th
percentiles}). Even so, this study was assigned a LoE 1b.

Treatment
There were no articles which strictly met our inclusion criteria.
Although there have been several articles on the potential of a
fish-oil-based fat emulsion (Omegaven, Fresenius Kabi AG,

Bad Homburg v.d.h., Germany) to reverse PNAC,54-56 none

have been proper case control/cohort prospective studies since
historical controls were used (LoE 4).

Discussion
There are many complications associated with PN, one of the
most common in infancy is PNAC.6 Similarly, IFALD is the

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most serious complication in patients with IF receiving longterm PN, and it is the most consistent negative prognostic indicator for overall survival in these patients.7
Nonetheless, many weak points are still present in the literature on both PNAC and IFALD. With regard to the definition of cholestasis and liver disease, they are conventionally
defined as CB 2 mg/dL (or 34 mol/L) in pediatric population. Although the cutoff value is considered arbitrary and does
not necessarily correlate with any specific hepatic pathology, it
has been extensively used in pediatric studies.28,46 Furthermore,
the definition of PNAC and IFALD are not standardized, even
if one of the most commonly definition used is CB 2 mg/dL
(or 34 mol/L) in association with a duration of PN 14
days.2,28,29,47 These brought to heterogeneity between different
studies in this field. Moreover, to the knowledge of authors, no
systematic review has been published on incidence, prevention, and treatment of PNAC and IFALD. As mentioned, an
up-to-date systematic review on -3 fatty acid lipid emulsions25 included nonhomogeneous articles on both PNAC and
IFALD without a definite definition of PNAC and IFALD.
Moreover, a systematic review on pediatric IF26 did not mention any definition of IFALD. We acknowledge that our a priori
definitions (eg, CB, length of time on PN) as inclusion criteria
for the systematic review may have excluded some relevant
articles, but this was necessary to decrease bias and potential
subjective inclusion or exclusion of articles.

association was first noted by Beale et al58 who showed that the
incidence of cholestasis (defined as CB 1.5 mg/dL) was 10%
after 10 days of PN but increased to 90% in those treated for >3
months. This correlation could also explain the higher incidence of IFALD in pediatric IF, because of the longer PN (ie,
PN > 28 days, Table 3b). However, because of the paucity of
studies included in Group 3, no further significant subanalysis
were feasible on the incidence of IFALD in patients with longterm PN.
There has been no obvious decrease in the incidence of both
PNAC and IFALD over the last 40 years. Because of the lack
of studies exclusively on preterm neonates (Group 1) and on
IFALD (Group 3), we could not achieve any consideration on
these patients (Figure 4a). With regard to the Group 2, patients
are heterogeneous in the populations of infants described, both
in terms of patient age and indication for PN (ie, surgical vs
medical). Furthermore, since most of the study periods are
overlapping, no strict decreasing incidence of PNAC was
reached in this group (Figures 4b and 4c). In addition, it must
be noted that there appeared to be a lack of recent data in incidence of both PNAC and IFALD during the second half of past
decade. Because of this, none of the articles that met our inclusion criteria used the novel lipids that have seen widespread
introduction over the past 5 years. It remains to be established
whether the use of such lipids could decrease the incidence of
PNAC.

Incidence

Prevention

Despite improvements in surgical procedures, intensive care

unit (ICU) management, involvement of nutrition support
teams, as well as in the composition and mode of delivery of
PN, both the incidence of PNAC and IFALD remain high with
special concern in young infants.56 In the present systematic
review, only articles with a homogenous definition of cholestasis related to PN and IF were included (Figure 2).
The overall incidence of PNAC and IFALD in the studies
included ranged from 0% to 74.4% (mean 29.9%). Because the
incidence of PNAC could be age-related, with a higher incidence in very-low-birth-weight infants, we separated studies
on ELBW and VLBW (Group 1) from remaining (Group 2). A
further group (Group 3) was assessed to articles exclusively
focused on IFALD. We did not notice any obvious relationship
between age of patient and incidence of PNAC, although only
a few articles included children (Table 3a). In contrast with
what we expected, preterm neonates in Group 1 demonstrated
a lower incidence of PNAC vs neonates, infants, and children
in Group 2 (25.5 vs 30.6%, respectively). This result could be
biased by not specified preterm neonates included in studies of
Group 2 (eg, Fok et al43 studied neonates with a mean birth
weight of 1347 g).
A further bias, given by different length of PN, was elucidated in the Group 2 (Figure 3): as expected the development
of PNAC is closely related to the duration of PN. This

Even though there have been numerous studies aimed at preventing PNAC or IFALD, many of these were excluded as they
were retrospective case series. There were only a few articles
in which interventions were prospectively evaluated. Moreover,
only some of them met our inclusion criteria to define PNAC.
As a result, no prospective studies on IFALD were included,
because of different (or lack) definition of the disease. There is
evidence of beneficial effect of the management by multidisciplinary teams with pediatric gastroenterology, pediatric surgery, transplant, and immunology.59 Advances such as the
introduction of multidisciplinary teams and protocolization, in
addition to specific therapeutic or surgical modulations, have
improved the outlook for both PNAC and IFALD has changed
considerably in the last decade; fewer children undergo intestinal transplantation and waitlist mortality for children listed for
intestine transplantation has also decreased.17,60,61
Choleretic agents. None of the 2 included studies on choleretic agents to prevent PNAC in Groups 1 and 2 of patients
showed a significant benefit to either TUDCA or CCK (Table
5).47,48 A previous study with lower doses of CCK (0.02 g/kg
per dose, i.v., every 12 hours for 14 days) failed to prevent
development of PNAC in severe preterm neonates.28 This article was excluded because authors compare prospective cases
with a historical cohort of controls (LoE 4).

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Further RCTs on PNAC in Group 262 and Group 163 of preterm neonates demonstrated that ursodeoxycholic acid
(UDCA) significantly decreased serum -glutamyl transferase
activity (a widely and early sensitive used marker in detecting
PNAC) during PN, associated with an earlier, albeit not significant, achievement of full enteral feeding. Both trials were
excluded from the systematic review as no definition of cholestasis was included. Even if the first study62 was a high-quality
RCTs (LoE 1b), the latter63 compared cases to control neonates
with significantly lower gestational age and birth weight
(LoE 2b). However, due to these encouraging results, the role
of UDCA in preventing PNAC may warrant further
investigation.
Antibiotic therapy.Intraluminal bacterial overgrowth with
subsequent translocation and sepsis, catheter related sepsis,
and any other conditions that produce a systemic inflammatory
response, such as NEC, are closely associated with PNAC.64
Despite this, studies with 2 doses of MNZ prophylaxis in
Group 2 of patients failed to show any benefit (Table 5).51
In contrast, both high and intermediate-dose of oral erythromycin (12.5 mg/kg/dose, and 5 mg/kg/dose every 6 hours for
14 days, respectively)49,50 were shown to decrease the incidence of PNAC and septicaemia in 2 RCTs on Group 1 of preterm neonates (Table 5). The meta-analysis on these 2 RCTs
(Figure 5) corroborates the beneficial effect of erythromycin in
preventing PNAC (P < .001). However, this effect may be
mediated via the prokinetic effects of erythromycin rather than
its antibiotic effects. Moreover, these results are homogeneous
to the significant evidence that high-doses of erythromycin,
even when administered orally, can reduce the time required by
premature infants with nonobstructive gastrointestinal dysmotility to achieve full enteral nutrition, and thus reduce their
dependence on PN. Furthermore, none of the RCTs published
so far reported any major side effects, in particular, hypertrophic infantile pyloric stenosis and life-threatening cardiac dysrhythmia.65 However, even if oral erythromycin was
demonstrated to reduce the incidence of PNAC in VLBW,
results obtained in this particular subset of patients could not
be extrapolated in neonates at term or in older group of patients
with IF (Groups 2 and 3). Furthermore, uncommon untoward
effects, long-term effects on the bowel microflora and the possibility of promoting emergence of multidrug-resistant organisms in the neonatal ICU, have not been fully evaluated,66 so
that oral erythromycin should be used cautiously and selectively in preterm infants at higher risk for PNAC.
Nutritional intake.A way to prevent PNAC is to reach full
enteral feeding and cease PN supplementation. Two RCTs
included in our systematic review on Group 1 preterm neonates (Table 5) investigated the use of early enteral feeds to
prevent PNAC in severe preterm neonates.30,33 Both RCTs did
not reach high LoE2band only the study on aminoacidfree PN with enteral bovine whey protein demonstrated

significant prevention of PNAC in comparison with controls.33

Even if the study was focused on severe preterm neonates
(Group 1), we believe that amino acid-free PN would not be
acceptable for any other than very individualized use, thus
restricting its employment in those who tolerate early enteral
feeds with premature infants formula added with whey
protein.
Furthermore, some,67,68 but not all,69,70 studies excluded
from this systematic review support early enteral feeding. All
studies but 168 were exclusively on Group 1 neonates and did
not meet the inclusion criteria because of short-term PN67,68,70
or lack of definition of PNAC.69 Moreover, the dated RCT by
Dunn et al67 demonstrated high risk of biases given by vague
inclusion and exclusion criteria and the small number of neonates involved (LoE 2b), and the RCT by Leaf at al68 included
a slightly higher proportion of infants 1250 g in the early
group. In addition, all these prevention studies were performed
predominantly or exclusively on severe preterm neonates
(Group 1),30,33,67,70 and some procedures (ie, early low volume
feeding or aminoacid-free PN with enteral whey proteins) are
not applicable in older children or in pediatric IF (Groups 2 and
3). Subsequently, further prospective studies are needed to corroborate the benefit of these procedures both in severe preterm
neonates and in older pediatric patients.
Although 2 retrospective articles39,71 on Group 2 of neonates (LoE 4) demonstrated that cyclic PN may be associated
with a decreased incidence or, perhaps, delay in onset of
PNAC, the RCT included on this manoeuvre52 did not reach
any beneficial effect in cycling PN to prevent PNAC in VLBW.
This result could be expected as the only difference between
the 2 groups was the length of administration of the amino acid
solution (over 20 hours in the group with cycle PN vs over 24
hours in those with continuous PN), with presumably the same
final daily amount of the solution in the 2 groups. Moreover,
the length of administration of the soybean-based lipid emulsion in both groups was equal (over 18 hours).
As well as specific interventions undertaken to prevent
PNAC or IFALD, there may be other ways to reduce its incidence. Sigalet et al72 showed in Group 3 of patients the importance of a multidisciplinary team and a protocol-driven strategy
to prevent IFALD. No episode of severe cholestasis (CB > 100
mol/L for > 2 months) occurred in the cohort of patients followed by the multidisciplinary team in comparison with an
incidence of 28% in an historical cohort of controls. However,
because of the presence of the historical cohort of controls, this
study did not meet our inclusion criteria (LoE 4).
Even if several improvements in components of PN have
been achieved throughout last decades, only 2 included articles
evaluated enhancements in elements of PN.43,53
In Groups 1 and 2 of patients, Vileisis et al53 demonstrated
that a LP regimen could be beneficial in reducing incidence of
PNAC. However, a LP regimen could have an adverse impact
on growth. Furthermore, the group of infants who presented
with cholestatic jaundice were exposed to a significantly longer

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PN and received also a significantly higher glucose supply as

compared with infants without cholestatic jaundice, thus
achieving a LoE 2b. Therefore, the role of aminoacid intake
was hardly assessed.
In a good-quality RCT (LoE 1b) on Group 1 neonates, Fok
et al43 showed that manganese supplementation in excess of
recommendations causes a more severe degree of conjugated
hyperbilirubinaemia. However, most centers use a trace element solution that provides manganese at recommended levels. It is not known whether a further decrease in manganese
intake could affect cholestasis.
In the same field, Spencer et al73 observed in post hoc data
analysis of a prospective study on Group 2 of infants (LoE 3b)
that taurine supplementation did offer a very significant degree
of protection against PNAC compared with no taurine.
However, as infant PN amino acid solutions now contain taurine, whether there could be any benefit of increased taurine
supplementation is unknown.
Even if glutamine supplementation during PN did not
reduce the incidence of sepsis in Group 2 of infants with surgical gastrointestinal disease,74,75 it is still debated whether its
role in the maintenance and repair of gastrointestinal mucosa
may prevent PNAC/IFALD by protecting the hepatic function.
A pilot RCT75 with inadequate sample size (LoE 2b) on Group
2 of infants with surgical gastrointestinal disease showed that
enteral glutamine supplementation had no apparent effect on
the duration of PN, tolerance of enteral feeds, or intestinal
absorptive or barrier function. However, a more recent RCT76
with insufficient sample size (LoE 2b) on Group 1 of infants
demonstrated that parenteral glutamine supplementation presents a protective effect on the liver by decreasing the serum
levels of aspartate aminotransferase and total bilirubin (P <
.05), even if no significant difference was noticed with regard
to direct bilirubin. High-quality RCT would be required to better assess the benefit of this maneuver.
There were a few articles evaluating the possible beneficial
effect of other elements of PN which were excluded because
they were retrospective, in patients on short-term PN, or
because of the lack of a clear definition of PNAC. Among
these, a medium-chain:long-chain triacylglycerol 50:50 mixture demonstrated some potential benefits in an adequate-quality
RCT (LoE 2b) on Group 2 of patients, excluded because of the
lack of definition of PNAC.77 This mixture could warrant further investigation.
A novel lipid emulsion containing a mixture of soybean oil,
medium-chain triglycerides, olive oil, and fish oil (SMOFlipid,
Fresenius Kabi, Bad Homburg v.d.h., Germany) showed some
benefits in a well-constructed RCT (LoE 1b) on Group 2
patients on short-term PN (7-14 days).78 Two RCTs of
SMOFlipid vs Intralipid for prevention of PNAC in Group 1 of
infants79 and in Group 2 of infants with IF/SBS80 are currently
ongoing.
Although early reports of success and safety with the use of
Omegaven in reversal of PNAC23,54-56 might suggest that it

may be useful in the prevention on PNAC, in a retrospective

analysis of prospectively collected data on Group 2 of neonates
Nasr et al81 have stated that with >80% of PNAC patients being
weaned from PN without adverse hepatic sequelae, it is difficult, in the absence of definitive evidence of efficacy and
safety for Omegaven together with increased costs, to justify
its routine use in a low-risk population (such as the surgical
neonates with mild parenteral nutritionassociated liver dysfunction examined in the study) outside formal research protocols. To this end, there are various RCTs on the use of new lipid
emulsions to prevent/treat PNAC or IFALD currently registered for recruitment. One RCT of Omegaven vs Intralipid in
preventing PNAC in Group 2 of infants with IF is currently
completed albeit not published.82

Treatment
Currently there is no truly effective pharmacologic management of both PNAC and IFALD. Maneuvers to treat these diseases are limited (bile acid-binding agents, choleretics such
as ursodiol, cycling of PN administration, and limitation of
trace minerals in PN) and have little supporting evidence in
infants. One RCT of UDCA vs placebo for treating PNAC in
Group 2 of neonates is currently recruiting participants.83
A prospective study from Cober et al84 demonstrated that an
intravenous (IV) fat emulsion reduction in PN to 1 g/kg/d 2
times per week in neonates diagnosed with PNAC significantly
decline the total bilirubin levels compared with controls (P <
.01) and significantly shortened the days on PN (P < .05).
However, because of the presence of the historical cohort of
controls, this study did not meet our inclusion criteria and
reached a low LoE (LoE 4).
The novel lipids described above have also been evaluated
for their ability to reverse PNAC/IFALD. There is increasing
enthusiasm because of the early reports of success and safety
with the use of Omegaven to reverse PNAC/IFALD in infants
and children.54-56,85-92 However, most of these studies were retrospective,85-87,92 prospective with no controls,88-90 or prospective with historical cohort of controls,54-56 so that there are no
current data from high-quality prospective RCTs.89,92 Three
studies from the same authors54-56 compared prospective
groups treated with the fish-oil-based fat emulsion vs historical
cohorts of infants (Group 2) treated with Intralipid (LoE 4).
Patients receiving Omegaven had a significantly higher reversal of cholestasis while on PN (P < .0001), also in the study
where the fat doses were identical in both groups.55 One RCT
of Omegaven vs Intralipid minimization for treating severe
PNAC in Group 2 of patients is currently ongoing.93
Furthermore, SMOFlipid, in an excluded good-quality RCT
(LoE 1b), significantly reduced total bilirubin levels compared
with Intralipid in infants and children (Group 2) receiving
home PN.94 Therefore, despite the promise that alternate lipid
strategies may have, at present the use of these novel lipids
remains investigational and should be restricted to those with

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severe PNAC/IFALD unless in the context of a RCT examining their safety and efficacy as a preventative strategy.89
Among choleretics, UDCA was tested in a few studies,95-99 although only 2 study designs were prospective,95,96
and only 1 of them was a case-control study, albeit retrospective97 (all studies at LoE 4). Thus none of these articles met our
inclusion criteria, even if UDCA may warrant further investigation as there appeared to be a reversal of cholestasis in all but
1 study.98 Two preliminary reports with no controls evaluated
the role of CCK in Group 2 of infants with PNAC.100,101 Both
of them showed that CCK appears to be associated with a
decline in CB levels, so that cholestasis may be reversed by IV
CCK in the majority of patients. Other studies not included in
our review (inclusion criteria not met) assessed the beneficial
effects of enteral nutrition together with ursodiol in Group 2 of
infants102 or with more composite intestinal rehabilitation program in Group 3 of patients.103,104 Even if none of these articles
were prospective neither case-control designed (LoE 4), all
achieved a reduction or reversal of cholestasis, which may
indicate the importance of an aggressive weaning of PN to
enteral nutrition in infants with both PNAC or IFALD.
Ultimately, irrigation of the biliary tract may provide benefits by flushing out unexcreted remnants; a retrospective casecontrol study (LoE 4) by Wales et al105 suggested that
percutaneous transhepatic transcholecystic cholangiography
may be effective in Group 2 of surgical neonates with PNAC.

Conclusions
The incidence of PNAC is directly correlated to the length of
PN. This correlation is corroborated by the higher incidence of
IFALD in pediatric IF, because of the longer PN. Despite
improvements in the management of infants and children
requiring PN and the control of infections, the incidence of
both PNAC and IFALD in children does not appear to have
decreased over the past 4 decades.
There is a lack of high quality prospective study to prevent/
treat these diseases, especially on IFALD. The only interventions which have been shown to significantly prevent development of PNAC are limited to severe preterm neonates. They
demonstrated benefits in preventing PNAC given by both high
and intermediate-dose of oral erythromycin49,50 or by an aminoacid-free PN associated with enteral feeding with premature
infant formula and whey protein.33 However, both maneuvers
might warrant additional examinations and further prospective
studies are mandatory to corroborate these results.
Omegaven and SMOFlipid may have benefits in prevention
and/or reversal of PNAC and IFALD, although the evidence
for their use is currently limited. Consequently, there is a
requirement for further RCTs to better assess prevention and
treatment maneuvers against both PNAC and IFALD in infants
and children. However, we acknowledge that sometimes performing RCTs is simply impossible, and then we are left with
lower levels of evidence. For example, the introduction of

multidisciplinary teams to treat patients with or at risk of

PNAC/IFALD has almost certainly improved the outcomes
and it would be unethical and impossible to design a study randomizing patients to receive or not receive care from such a
team. Similarly, in Europe at least, where novel lipids were
initially licensed and already very widely used, it is extremely
difficult to design an RCT of treatment of established PNAC/
IFALD where 1 arm would exclusively receive soy-based lipids. In scenarios such as these prospective or retrospective
studies, despite offering lower levels of evidence, may be the
best we can hope for. One other possibility for these rare disorders is to expand the role of registries. A registry exists for the
STEP procedure, for example, but its effectiveness is limited
by the lack of comparative data (eg, alternative surgical procedures, medical therapy, etc).

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