GASTROENTEROLOGY 2006;130:S70 –S77
Intestinal Failure–Associated Liver Disease: What Do We Know
Today?
DEIRDRE A. KELLY
The Liver Unit, Birmingham Children’s Hospital, NHS Trust, Birmingham, England
Intestinal failure–associated liver disease develops in
40% to 60% of infants who require long-term total par-
enteral nutrition (TPN) for intestinal failure and 15% to
40% of adults on home parenteral nutrition. The clinical
spectrum includes hepatic steatosis, cholestasis, chole-
lithiasis, and hepatic fibrosis. Progression to biliary cir-
rhosis and the development of portal hypertension and
liver failure occurs in a minority but is more common in
infants and neonates than in adults. The pathogenesis is
multifactorial. In infants it is related to prematurity, low
birth weight, duration of PN, short bowel syndrome re-
quiring multiple laparotomies, and recurrent sepsis.
Other important mechanisms include lack of enteral
feeding, which leads to reduced gut hormone secretion;
reduction of bile flow and biliary stasis, which leads to
the development of cholestasis; and biliary sludge and
gallstones, which exacerbate hepatic dysfunction. In
adults, IFALD is less common and related to age, length
of time on PN, total caloric intake, and lipid or glucose
overload. In preterm infants, a deficiency of taurine or
cysteine may play a role, whereas in both adults and
children, choline deficiency may exacerbate IFALD. Lipid
emulsions, choline deficiency, and manganese toxicity
are associated with both hepatic steatosis and cholesta-
sis in adults and children. Management strategies for
the prevention of intestinal failure–induced liver disease
include early enteral feeding, a multidisciplinary ap-
proach to the management of parenteral nutrition, and
aseptic catheter techniques to reduce sepsis. The addi-
tion of choline, taurine, and cysteine to PN solutions
may also play a role. Oral administration of ursodeoxy-
cholic acid may improve bile flow and reduce gallblad-
der stasis. Survival after either isolated small bowel or
combined liver and small bowel transplantation is ap-
proximately 50% at 5 years, making this an acceptable
therapeutic option in adults and children with irrevers-
ible liver and intestinal failure.
he development of parenteral nutrition (PN) has
T altered the outcome for neonates and infants with
intestinal failure either from congenital abnormalities or
extensive gastrointestinal surgery.1,2 Refinements in par-
enteral solutions have now reduced the metabolic com-
plications, making the administration more straightfor-
ward. Improvements in catheter design with double- and
triple-lumen catheters in addition to aseptic placement
techniques using trained personnel have reduced septic
complications.3–5 Hepatobiliary dysfunction remains a
significant life-threatening complication and is an im-
portant indication for combined liver and small bowel
transplantation.
Hepatic dysfunction secondary to intestinal failure
(IFALD) differs in adults and children. Cholestasis occurs
in 40%– 60% of infants, steatosis in 40%–55% of adults,
and biliary sludge and cholelithiasis occurs in both adults
and children.6 –11 The etiology is multifactorial (Table 1),
and the incidence varies according to the population.
Hepatic Steatosis
Hepatic steatosis is associated with hepatic accu-
mulation of lipid or glycogen from excess calories
(⬎8 –12 mg/kg/d of glucose).12 It is thought that par-
enteral carbohydrate calories are converted to triglycer-
ide, perhaps by stimulating insulin release or by lipo-
genesis and the sythesis of acylglycerol from glucose as
shown in rats.13 Histology of the liver reveals fatty
infiltration of hepatocytes, which is reversible after re-
duction of calories.14 Hepatitic steatosis may also be
related to excess lipid infusions15; deficiencies of essential
fatty acids; choline, taurine, or glutathione16,17; or pho-
toxidation of parenteral vitamins as shown in rats.18
Cholestasis
The development of cholestasis is related to a
number of factors. In infants, it is associated with pre-
maturity, recurrent sepsis, lipid emulsions, and possibly
lack of enteral feeding.3,19 –24 It is also associated with the
number of laparotomies, number of days on antibiotics,
and delayed start to enteral feeding.25
Abbreviations used in this paper: IFALD, hepatic dysfunction second-
ary to intestinal failure; PN, parenteral nutrition; TPN, total parenteral
nutrition.
© 2006 by the American Gastroenterological Association
0016-5085/06/$32.00
doi:10.1053/j.gastro.2005.10.066
February Supplement 2006
Table 1. Intestinal Failure–Associated Liver Disease
Etiology
Prematurity and low birth weight
Duration of PN
Length of bowel remnant
Reduced enterohepatic circulation
Lack of enteral feeding
Recurrent sepsis
Toxic components of PN (⫹/⫺ peroxidation)
Protein under nutrition
Deficiencies of
Essential fatty acids
Chlorine
Excess
Dextrose
Lipid emulsion ⬎1 g/kg/d
The earliest clinical sign is a rise in conjugated bili-
rubin particularly during episodes of intercurrent sep-
sis23 associated with an increase in alkaline phosphatase,
amino transferases, and gamma glutamyl transpepti-
dase.7 Many studies have noted the close relationship
between the development of IFALD, prematurity, and
low birth weight.23,26 Because many infants requiring
total parenteral nutrition (TPN) are likely to be prema-
ture with low birth weight, it is difficult to be certain
whether these are independent risk factors or associated
factors.
The development of cholestasis is closely related to
birth weight and duration of TPN as demonstrated by
Beale et al26 who reviewed 62 premature infants on TPN.
The overall incidence of cholestasis was 23%, but infants
receiving therapy for more than 60 days had an incidence
of 80% increasing to 90% in those treated for more than
3 months. The incidence of cholestasis was 50% in
infants with birth weight ⬍1000 g but decreased to 7%
if birth weight was ⬎1500 g. This has recently been
confirmed by Beath et al23 who found the highest inci-
dence in infants with less than 34-week gestation and
who weighed less than 2 kg.
The increased incidence of IFALD in premature babies
suggests that the development of hepatic dysfunction
may be related to immaturity of the neonatal liver. It is
known that in premature infants the total bile salt pool
is reduced. There is both diminished hepatic uptake and
synthesis of bile salts and a reduced enterohepatic circu-
lation as compared with full-term infants or adults.27 It
is possible that other essential components of bile secre-
tion such as glutathione may be reduced in the newborn
because hepatic glutathione depletion has been shown in
young animals on TPN.28
Sulphation, which is an important step in the solubi-
lization of toxic bile salts such as lithocholic acid, is
deficient in the fetus and neonate.29 In rats, lithocholic
INTESTINAL FAILURE–ASSOCIATED LIVER DISEASE S71
acid has been shown to produce bile duct hyperplasia,
gallstone formation, and intrahepatic cholestasis.30,31 It
is therefore possible that the liver and biliary system of
the premature infant is more susceptible to toxic damage
from lithocholic acid or other toxic bile salts.
In adults, cholestasis has been associated with the
residual length of the bowel (⬍50 cm), perhaps because
of the difficulty in achieving intestinal adaptation and
sufficient enteral feeding in such a short gut leading to
long-term dependence on PN. Alternatively, there may
be interruption of the enterohepatic bile salt circulation
leading to abnormal bile acid metabolism or the short or
diseased gut may be more prone to bacterial translocation
and systemic sepsis.11 A prospective study that evaluated
the prevalence of liver disease in adults on home paren-
teral nutrition for permanent intestinal failure associated
the development of cholestasis to lipid infusions of ⬎1
g/kg/d.7 The relationship between cholestasis and lipid
emulsions has been described in both adults and chil-
dren.6,7,24 The mechanism is speculative, but suggestions
include macrophage activation caused by excess w-6
polyunsaturated fatty acids in intralipid leading to an
accumulation of hepatic phospholipids and/or phy-
tosterols.7,24,32
Lack of Enteral Intake
The inability to establish enteral feeding is com-
mon in children requiring parenteral nutrition and is one
of the main indications for TPN. IFALD appears to
develop more frequently in those children who are unable
to tolerate any enteral feeding compared with those who
are partially enteral fed, although more recent studies
suggest that recurrent sepsis may be a more important
mechanism.3,21,23
Experimental studies have shown that short-term fast-
ing has several metabolic and endocrine consequences on
intestinal and liver function. Levels of gastrointestinal
hormones, such as gastrin, motilin, glucose-dependent
insulinotropic polypeptide, secretin, pancreatic polypep-
tide, glucagons, and vasoactive intestinal peptide, are
reduced in patients on TPN who are not being enterally
fed.33 This may lead to reduced gallbladder contractility
and the development of intestinal stasis.33–35 Intestinal
stasis is associated with bacterial overgrowth, bacterial
translocation, sepsis (which may exacerbate cholestasis in
infants23,36), and the production of lithocholic acid
(which has been shown to be toxic to the liver in
rats30,31). There is no evidence that prolonged PN use per
se leads to bacterial translocation.37
The reduction in cholecystokinin release may influence
gallbladder size and contractility and cause the develop-
S72 DEIRDRE A. KELLY
ment of biliary sludge.38 – 40 It is also possible that fasting
reduces the size of the bile salt pool and bile formation
compounding the difficulties with gallbladder contrac-
tility and the formation of sludge.32
Sepsis
IFALD is more common in neonates who have
recurrent episodes of sepsis whether this is related to
central line infections or bacterial translocation from
bacterial overgrowth.19,20,22,23,41 Bacterial overgrowth
from intestinal stasis has been related to the development
of IFALD possibly because of the combination of the
reduction in bile flow, the production of secondary bile
salts, and sepsis from bacterial translocation. A review of
8 fatal cases of progressive liver failure in surgical neo-
nates indicated that the hepatic failure was closely related
to septic episodes and/or peritonitis.42
Components of TPN
IFALD may be related either to a deficiency or
excess of amino acids or lipid in the TPN solutions. It is
possible that hepatotoxicity may be caused by a defi-
ciency of taurine or cysteine, which are conditional es-
sential amino acids in neonates because of the low levels
of hepatic cystathionase and cysteine sulfinic decarbox-
ylase.43 In older infants and adults, cysteine and taurine
are synthesized from methionine but this production is
diminished in premature infants.44 Not only is taurine
one of the main bile acid conjugates in the neonate, but
it has been shown to increase bile flow and protect
against lithocholate toxicity. Despite this, the benefits of
taurine supplementation are unproven.45 Of interest is
the suggestion that choline deficiency may exacerbate
hepatic steatosis in adults and children. In a pilot study,
the addition of 2 g of choline chloride reduced steatosis
in adults as shown by normalization of hepatic transami-
nases and computed tomography scans.46
Toxic Components of TPN
Historically, the degradation of tryptophan in
TPN solutions contaminated by sodium bisulphate was
thought to produce cholestatic metabolites, but this does
not occur with modern solutions. Although aluminium
toxicity is well recognized in TPN and may lead to bone
disease, there is no evidence that it is implicated in TPN
liver disease.47,48
Chromium toxicity, secondary to TPN, has been re-
ported in animals. Both serum and urine chromium
concentration levels are higher in children on long-term
TPN compared with control values, although there was
no correlation with liver disease.49 –52
GASTROENTEROLOGY Vol. 130, No. 2
Manganese Toxicity
A number of recent studies have reported the
effects of manganese toxicity in children on long-term
TPN.51,52 Fifty-seven children receiving long-term TPN
including the multitrace element solutions of Pedel or
Addamel (KabiVitrum, UK) were studied.52 Forty-five
children (79%) had whole-blood manganese concentra-
tions above the reference range. Children with impaired
liver function had the highest manganese levels, and
there was a significant correlation between whole-blood
manganese levels, aspartate aminotransferase (r ⫽ 0.63,
P ⱕ 0.001), and total plasma bilirubin (r ⫽ 0.64, P ⱕ
0.001). Eleven children had both hypermagnasemia and
cholestasis, and 4 of these died. In the 7 survivors,
whole-blood manganese declined when manganese sup-
plements were reduced or withdrawn,52 and there was a
resolution of both brain and liver disease.53 Because
manganese is excreted in bile, the toxic effect may be
exacerbated in cholestasis and thus monitoring of man-
ganese levels is important in patients with IFALD cho-
lestasis.
Lipid Emulsions
There is now some evidence that lipid emulsions
induce cholestasis as well as steatosis. It has been ac-
cepted that excess lipid calories (the lipid overload syn-
drome) may lead to hepatic steatosis, hyperlipidemia,
and thrombocytopenia and that close monitoring of tri-
glyceride levels was necessary to monitor lipemia in both
adults and neonates with hepatic dysfunction.7,54
More recently, Colomb et al55 correlated episodes of
cholestasis in 23 infants with alteration in lipid concen-
tration, whereas Cavicchi et al7 showed that cholestasis in
adults was related to the use of ⬎1 g/kg/d of lipid. It has
been suggested that the mechanism may be caused by a
direct effect of lipid on hepatocytes,56 accumulation of
phospholipids7 or phytosterols,32 or production of in-
flammatory cytokines.57
Biliary Sludge and Gallstones
Acalculous cholecystitis, biliary sludge, gallblad-
der distention, and gallstones have been reported in
adults and children on long-term TPN.1,38,39 The inci-
dence of biliary sludge increases with duration of TPN
increasing from 6% at 3 weeks to 100% at 6 to 13
weeks58 as does the incidence of gallstone formation,39
particularly in children who have had ileal resection or
disease.39 The increase in gallbladder size noted in par-
enterally fed infants when compared with enterally fed
infants40 is related to the reduction in cholecystokinin
production and other gut hormones.35
February Supplement 2006
Gallbladder stasis may be prevented by the adminis-
tration of cholecystokinin or by stimulating endogenous
release of cholecystokinin through pulsed infusions of
amino acids or by any enteral nutrition, even 5 to 10
mL/h.59 Therapeutic administration of cholecystokinin is
not always useful and should be balanced against the side
effects, which include leucopenia, transient headache,
dizziness, abdominal pain, and nausea.60
Clinical Features
Early hepatic dysfunction is asymptomatic, but
jaundice is an obvious sign of cholestasis and fluctuations
in serum bilirubin may be related to septic episodes.23
Persistent elevation of serum bilirubin (⬎200 ␮mol/L,
⬎12 mg/dL) has an adverse prognosis.8,23,61,62 In 22
children who were evaluated for combined liver and
small bowel transplantation, a raised plasma bilirubin
concentration (⬎200 ␮mol/L, ⬎12 mg/dL) predicted
death from liver failure within 6 months in the 11
children who subsequently died of liver failure.62 In an
adult study 6 out of 42 patients on home PN developed
end-stage liver disease and died within 10 months of the
first bilirubin elevation.8
Hepatic dysfunction with portal fibrosis and spleno-
megaly develops gradually and may not be associated
with jaundice in infants. In 37 children referred for small
bowel and liver transplantation, splenomegaly was a
constant feature in 75% of this group irrespective of
cholestasis. Despite fairly extensive hepatic fibrosis and
splenomegaly, oesophageal varices are infrequent in these
children.24,61,62
In adults, clinical features are unusual unless signifi-
cant hepatic dysfunction develops with hepatomegaly.
Jaundice is a late sign, but abnormal hepatic transami-
nases occur in 39% of patients on long-term PN.11 It is
Figure 1. TPN steatosis with early cholestasis.
INTESTINAL FAILURE–ASSOCIATED LIVER DISEASE S73
Figure 2. End-stage liver disease showing biliary cirrhosis without
portal inflammation or fatty infiltration.
not clear why cholestasis and liver failure are more com-
mon in children, but this may be related to immaturity
of the neonatal liver, increased frequency of the short
bowel syndrome in this age group, or bacterial translo-
cation leading to sepsis and hepatic damage. The devel-
opment of hepatic dysfunction in all patients on PN
should be vigorously investigated for other causes of liver
disease before assuming this diagnosis.
Histology
The histopathological changes of IF-associated
cholestasis present a spectrum from hepatic steatosis to
biliary cirrhosis. Hepatic steatosis is more common in
adults and may develop without evidence of inflamma-
tion, cholestasis, or hepatocyte necrosis.14 Hepatic ste-
atosis is less common in infants who are more likely to
present with centrilobular cholestasis, portal inflamma-
tion, and necrosis with or without fatty infiltration. More
advanced liver disease has been described in children who
are being evaluated for combined liver and small bowel
transplantation and include portal fibrosis (100%), peri-
cellular fibrosis (95%), and bile ductular proliferation
(90%). Pigmented Kupffer cells (81%) and portal bridg-
ing (86%) were also prominent features. Cholestasis is
not always present. Biliary cirrhosis is a late development
that may be associated with death within 6 months61,63
(Figures 1 and 2).
Management
IFALD is potentially reversible if enteral feeding
can be resumed and the TPN discontinued before the
development of severe fibrosis or cirrhosis.64 In many
children and adults, this is not possible and prevention or
treatment of IFALD includes a number of approaches,
S74 DEIRDRE A. KELLY GASTROENTEROLOGY Vol. 130, No. 2

Table 2. Intestinal Failure–Associated Liver Disease To improve bile flow and reduce the formation of
Prevention and Treatment biliary sludge, oral ursodeoxycholic acid may be advan-
Encourage enteral feeding tageous and is commonly prescribed although there is no
Reduce duration of PN
Reduce bacterial overgrowth
clear evidence of efficacy. Spagnuolo and colleagues75
oral decontamination/probiotics fiber/glutamine report biochemical resolution in 7 children on long-term
Central line care PN treated with ursodeoxycholic acid, but another study
multidisciplinary aseptic approach
Ursodeoxycholic acid 15–20 mg/kg
in infants given ursodeoxycholic acid prophylactically to
prevent liver dysfunction found no benefit.76 However,
in a prospective study of adults on PNS, ursodeoxycholic
acid was associated with improved liver function tests.77
although not all have been proven to be successful (Ta-
ble 2). Intestinal Adaptation and Liver Dysfunction
The introduction of some enteral feeding will encour-
age normal biliary dynamics, decrease gallbladder size, It is possible that the presence of liver dysfunction
and improve bile flow,40 which may improve cholestasis. and portal hypertension may prevent adequate intestinal
Other strategies include the prevention of bacterial over- adaptation. Weber and colleagues78 showed that survival
growth by the addition of fiber to enteral feeds if toler- and time to the development of feeding tolerance was
ated because this may reduce bacterial translocation and related to severity of liver dysfunction, whereas a number
thus systemic sepsis.65 of authors have drawn attention to the improvement in
The addition of glutamine to TPN solutions may feeding intolerance after isolated liver transplantation in
reduce the effect of septic episodes on hepatic function children with severe IFALD,79,80 suggesting that this
because glutamine reverses the inhibition of hepatocyte option should be considered in children with potentially
mitochondrial metabolism observed in endotoxemia in adaptable intestines.
rats.66 Glutamine may also protect against TPN-related
hepatic dysfunction by improving gut immunity67 be- Small Bowel Transplantation
cause the addition of glutamine to TPN solution has Because over 500 small bowel operations have
been shown to attenuate TPN-associated gut hypoplasia been carried out worldwide with a 5-year survival of over
and to prevent PN-related depletion of immunoglobulin 50%, it is important to consider this therapeutic option
A–producing gut lamina propria plasma cells.68 Glu-
in children with intestinal failure.81 Current results sug-
tamine also may have an effect by reducing intestinal
gest that isolated small bowel transplantation is as suc-
permeability and thus reducing bacterial translocation in
cessful as combined small bowel and liver transplantation
rats.69 It is unclear whether glutamine has a separate
in both adults and children, although multivisceral
effect on intestinal adaptation,68 but in preterm infants
the addition of glutamine to PN reduced the time to full transplantation has less long-term survival (Figure 3).82
enteral feeding whereas enteral glutamine addition re-
duced the incidence of infection.70,71
Alternatively sacchromyces boulardii, which is a non-
pathogenic yeast, may reduce bacterial translocation ei-
ther by increasing intestinal immunoglobulin A secre-
tion or reducing bacterial overgrowth.72 If enteral
feeding is impossible, reducing the duration of daily PN
or using cyclic infusions may be helpful.73 If cholestasis
is severe, restriction of lipid intake and control of man-
ganese and copper levels are important.
The most important strategy is the prevention of
sepsis.74 There is a marked difference between the inci-
dence and the age of development of liver disease in
children whose central line catheter care is managed by
units with nutritional care teams with experience in
parenteral nutrition,62 and strict catheter care and reduc-
tion of central line infections is an important preventa- Figure 3. Survival after intestinal transplantation in children (Intes-
tive mechanism in the development of TPN liver disease. tine Transplant Registry).
February Supplement 2006
Summary
IFALD is more common in infants and children
than in adults. Important mechanisms in infants include
prematurity, length of remaining bowel, and recurrent
sepsis, whereas in adults it is related to the length of time
on PN and excess caloric intake of glucose and lipids.
Despite recent advances in management and administra-
tion of PN, much more still needs to be learned to
prevent the development of life-threatening liver disease.
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Received July 27, 2004. Accepted October 18, 2005.
Address requests for reprints to: Deirdre A. Kelly, MD, FRCP, The
Liver Unit, Birmingham Children’s Hospital, NHS Trust, Steel-
house Lane, Birmingham B4 6NH, United Kingdom. e-mail:
Deirdre.Kelly@bch.nhs.uk; fax: (44) 0-121-333-8251.