ARTICLE

Effect of Ursodeoxycholic Acid on Liver Function in

Children After Successful Surgery for Biliary Atresia
Stephanie Willot, MDa, Stephanie Uhlen, MDa, Laurent Michaud, MDa, Gilbert Briand, MD, PhDb, Michel Bonnevalle, MDc, Rony Sfeir, MDc,
Frédéric Gottrand, MD, PhDa

Departments of aPediatric Gastroenterology, Hepatology, and Nutrition and cPediatric Surgery, Lille University Children’s Hospital, Lille, France; bBiochemistry Laboratory,
Site Eurasanté, Lille University Hospital Center, Lille, France

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject What This Study Adds

UDCA is a hydrophilic bile acid that improves clinical and biological parameters when This study demonstrates, using a discontinuation/reintroduction methodology, that
used in various cholestatic diseases of adults and children. The effects of long term UDCA UDCA therapy results in improvement of liver function in children with biliary atresia
therapy in children with biliary atresia have not been studied. who had a successful surgery and that these beneficial effects persist for several years
after the Kasai intervention.

ABSTRACT
OBJECTIVES. Although ursodeoxycholic acid has been used to treat various cholestatic
liver diseases in children, few data are available about its efficacy in biliary atresia.
The aim of this study was to assess the effect of ursodeoxycholic acid treatment on www.pediatrics.org/cgi/doi/10.1542/
peds.2008-0986
liver function in children who underwent successful surgery for biliary atresia.
doi:10.1542/peds.2008-0986
PATIENTS AND METHODS. We prospectively studied 16 children with biliary atresia who Key Words
underwent successful portoenterostomies (postoperative conjugated bilirubin con- biliary atresia, ursodeoxycholic acid,
centration: ⬍34 ␮mol/L) and were treated with ursodeoxycholic acid for at least 18 cholestasis, bile acids, portoenterostomy,
liver enzymes, cirrhosis
months after surgery. Ursodeoxycholic acid treatment was then discontinued. Clin-
ical and biological assessment was performed at the time of discontinuation of Abbreviations
BA— biliary atresia
ursodeoxycholic acid treatment (T0), at follow-up (T1) and, if the clinical or biolog- UDCA— ursodeoxycholic acid
ical status worsened, after resumption of ursodeoxycholic acid treatment (T2). ALT—alanine aminotransferase
AST—aspartate aminotransferase
RESULTS. Ursodeoxycholic acid treatment was resumed in 13 cases. In 1 patient, jaun- GGT—␥ glutamyl transpeptidase
dice recurred after ursodeoxycholic acid therapy was discontinued but abated after Accepted for publication Aug 20, 2008
resumption of treatment. In 13 children, liver function worsened significantly when Address correspondence to Frédéric Gottrand,
ursodeoxycholic acid was discontinued. T1 versus T0 concentrations expressed as MD, PhD, Département de gastroentérologie,
hépatologie et nutrition pédiatrique, Hôpital
multiples of the upper limit of the normal range (in parentheses) were as follows: Jeanne de Flandres, CHRU Lille, 59000 Lille,
alanine aminotransferase, 3.0 ⫻N (0.8 –7.0) vs 1.5 ⫻N (0.5–5.4); ␥ glutamyl France. E-mail: fgottrand@chru-lille.fr
transpeptidase, 8.0 ⫻N (1.8 –30.2) vs 4.2 ⫻N (0.5–27.4); and aspartate aminotrans- PEDIATRICS (ISSN Numbers: Print, 0031-4005;
ferase, 1.7 ⫻N (0.7– 6.0) vs 1.3 ⫻N (0.6 –3.4). When ursodeoxycholic acid treatment Online, 1098-4275). Copyright © 2008 by the
American Academy of Pediatrics
was resumed, liver function had improved in all patients by T2. Concentrations of
endogenous bile acids tended to be elevated at T1 (not significant) and were signif-
icantly decreased at T2.

CONCLUSION. Our study demonstrates the beneficial effect of ursodeoxycholic acid on liver function in children after
successful surgery for biliary atresia. Pediatrics 2008;122:e1236–e1241

B ILIARY ATRESIA (BA) is characterized by fibrosis and partial or complete obliteration of the extrahepatic biliary
tree within the first 3 months of life. The incidence of BA is 1 in 8000 to 1 in 20 000 births, making it the most
common cause of neonatal cholestasis.1 The only therapeutic option for reestablishing bile flow in children with BA,
the Kasai procedure or hepatoportoenterostomy, consists of resection of the entire extrahepatic biliary duct and
anastomosis of an intestinal loop to the porta hepatis. Although the Kasai intervention is successful in ⬃40% of
patients,2,3 most children develop chronic liver disease and BA is the first indication for liver transplantation in
children.4,5 Although up to 30% of patients with BA survive until adulthood without undergoing liver transplanta-
tion,6,7 their management, especially adjunct medical therapy, is not standardized.8 The 3 major concerns after the
Kasai intervention has been performed are prevention of bacterial cholangitis, optimization of nutritional status, and
improvement of choleresis. Ursodeoxycholic acid (UDCA) is a potential candidate for improvement of choleresis.
UDCA is a hydrophilic bile acid that comprises only 1% to 4% of total bile acids in humans. When used to treat
adults with primary biliary cirrhosis, UDCA improves clinical, biological, and histologic parameters9; decreases the
need for transplantation; and improves survival.10,11 Beneficial results of UDCA treatment have also been observed

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in patients with primary sclerosing cholangitis.12,13 Al-
though less frequently studied, UDCA treatment im-
proves the clinical and biological status of children with
cholestasis associated with cystic fibrosis,14,15 progressive
intrafamilial intrahepatic cholestasis,16 and cholestasis
associated with parenteral nutrition.17,18 Because of the
reported beneficial effects of UDCA treatment on various
cholestatic liver diseases and high tolerance of UDCA,
we hypothesized that UDCA treatment would be bene-
ficial for children with BA. However, the few studies that
have addressed this possibility were not controlled, were
conducted using limited numbers of patients, and as-
sessed the efficacy of UDCA during the perioperative
period early in life.19,20 There is little empirical basis for
prolonged UDCA therapy of children with BA because
the effects of long-term UDCA therapy have not been
studied. The aim of this study was to assess the effect of
UDCA on liver function in children more than a year
after successful surgery for BA.
PATIENTS AND METHODS
Because all children at our center are routinely treated
with UDCA shortly after surgery, we decided to use a
discontinuation/reintroduction methodology to assess
the efficacy of UDCA treatment. Treatment was stopped
and reintroduced when clinically indicated.
All patients with BA who underwent a successful
Kasai portoenterostomy at our hospital were considered
for inclusion in the study. The diagnosis of BA was
established by examining the bile ducts at the time of
surgery and by histologic study of the extrahepatic bile
duct remnants. Patients were eligible for inclusion in the
study if the Kasai procedure was successful and if they
were treated with UDCA for ⬎1 year. A successful Kasai
intervention was defined as resolution of jaundice 6
months after surgery (conjugated bilirubin concentra-
tion ⱕ34 ␮mol/L). All patients were treated with UDCA
at a dose of 200 mg/m2 of body area 3 times daily (600
mg/m2 per day) from the time of surgery until inclusion
in the study.21 The mean dose was 25 mg/kg per day
(range: 20 –36 mg/kg per day). None of the patients
received postoperative steroid treatment. After informed
consent of the parents, the decision to discontinue the
drug was made by the attending physician based on each
patient’s clinical and biological stability. One physician
evaluated all children during the study. After UDCA
treatment was discontinued, the children were prospec-
tively studied every 6 months. UDCA treatment was
reintroduced if a child’s clinical or biological status wors-
ened on follow-up; for these patients, a new clinical and
biological assessment was performed 6 months later.
The primary objective of the study was to assess the
clinical and biological efficacy of UDCA treatment. The
main clinical parameters evaluated were clinical jaun-
dice, pruritus (based on the presence of skin lesions and
parents’ evaluation), and bacterial cholangitis. The pres-
ence and size of hepatomegaly or splenomegaly (as-
sessed by using a tracing cloth applied to the abdomen)
was also noted during each evaluation. The following
biochemical parameters were assessed: serum concen-
trations of alanine and aspartate aminotransferase (ALT
Downloaded from www.aappublications.org/news at Indonesia:AAP Sponsored on December 4, 2019
and AST) and ␥ glutamyl transpeptidase (GGT), concen-
trations of total and conjugated bilirubin, total serum
bile acid, cholic and chenodeoxycholic bile acids, pro-
thrombin times, and levels of factor V. Serum liver en-
zyme concentrations were normalized to laboratory ref-
erence values and are expressed as multiples of the
upper limit of normal for age. Enrichment of serum bile
acids with UDCA was assessed by using gas chromatog-
raphy to ensure that treatment was correctly applied or
discontinued as appropriate. Serum samples for bile acid
analysis were obtained during fasting. Concentrations of
endogenous bile acids (cholic and chenodeoxycholic ac-
ids) in serum were also determined by using gas chro-
matography. After extraction of bile acids from serum
samples by using reverse-phase octadecyl silane-bonded
silica cartridges and hydrolysis with cholylglycine hydro-
lase, samples underwent gas chromatography to sepa-
rate chenodeoxycholic, ursodeoxycholic, and cholic ac-
ids.22 The concentrations of these bile acids are expressed
as percentages of total bile acid concentrations. The con-
centration of endogenous bile acids was estimated as the
product of the concentration of serum total bile acid and
the percentage of cholic and chenodeoxycholic bile acids.
Clinical and biological assessment was performed at
the time of discontinuation of UDCA (T0) and at 6
months thereafter. If the patient evidenced no clinical or
biological impairment, the examination was repeated
every 6 months. The T1 parameters were the last to be
obtained before UDCA was reintroduced, or, if UDCA
was not reintroduced, before the end of the study. If the
child’s clinical or biological status worsened, UDCA was
reintroduced and a new evaluation performed 6 months
later (T2). Clinical worsening was defined as recurrence
of jaundice, appearance of cholangitis or ascitis, and/or
exacerbation of pruritus. Biological status worsening
was defined as abnormal serum conjugated bilirubin
(⬎34 ␮mol/L) and/or a 50% increase of ALT or AST
compared with baseline values or GGT twice upper the
normal range.
The nonparametric Wilcoxon test was used to com-
pare the data for each patient at various times during the
study: before (T0) and after (T1) UDCA was discontin-
ued and before (T1) and after (T2) UDCA was reintro-
duced. P ⬍ .05 was considered significant. All data are
expressed as medians and ranges.
RESULTS
Since 1995, 28 children underwent Kasai procedures for
biliary atresia in our hospital. Among them, 16 fulfilled
the criteria for inclusion in our study. The other 12
patients were considered as surgery failure, because
their jaundice did not disappear after Kasai procedure.
The parents of all 16 children gave their consent for
them to be included in the study. The children (8 boys
and 8 girls) were enrolled in the study between Novem-
ber 1999 and June 2005. Four patients had associated
malformations of the urinary tract (vesico-ureteral mal-
formations, n ⫽ 3; hypospadias, n ⫽ 1); 1 patient had a
preduodenal portal vein, and 1 had limb abnormalities
and a cleft palate. The children underwent hepatopor-
toenterostomy at a median age of 54 days (range: 14 – 89
PEDIATRICS Volume 122, Number 6, December 2008 e1237
 TABLE 1 Characteristics of Patients at the Time of Discontinuation of UDCA Treatment
Patient Gender Age Weight (SD for Height (SD for Pruritus HMG SMG Portal
Height) Age) Hypertension
1 M 1 y, 6 mo 1.1 0.3 Y Y N N
2 M 1 y, 10 mo ⫺0.7 ⫺1.7 N Y N N
3 F 2 y, 11 mo ⫺0.8 1.2 N Y N N
4 M 1 y, 3 mo 1.2 ⫺1.7 Y Y Y Y
5 M 2 y, 3 mo 3.0 0.6 Y Y Y Y
6 M 2y 0.9 ⫺0.7 N Y N N
7 F 5y 1.4 2.7 N Y Y Y
8 M 5 y, 6 mo 0.4 0.9 N N N N
9 F 6y 1.6 0.2 Y Y Y Y
10 F 2 y, 5 mo ⫺1.1 0 N Y N N
11 F 3 y, 3 mo ⫺0.2 0.1 Y Y N N
12 F 5 y, 5 mo ⫺2.4 2.2 N Y N Y
13 M 2 y, 7 mo 0.3 1.6 N Y N Y
14 F 2 y, 6 mo ⫺0.7 0.4 Y Y Y Y
15 M 7 y, 3 mo ⫺0.4 ⫺0.4 Y Y Y Y
16 F 2 y, 9 mo ⫺0.9 ⫺1.2 N Y Y Y
HMG indicates hepatomegaly; SMG, splenomegaly; M, male; F, female; Y, yes; N, no.

days). Table 1 shows the patients’ clinical characteristics
at inclusion in the study. The median age at the time of
discontinuation of UDCA treatment (T0) was 2.7 (range:
1.5–7.2) years and children were treated with UDCA for
a median of 2.6 (range: 1.5–7.0) years. On entry into the
study, the median weight was 0.1 (⫺2.4 to 3.0) SDs, and
median height was 0.3 (⫺1.7 to 2.7) SDs. All but 1 child
had hepatomegaly, 7 had splenomegaly, and 9 had por-
tal hypertension, which was defined as the presence of
splenomegaly and/or esophageal varices, assessed by us-
ing endoscopy. One of 9 children with portal hyperten-
sion was treated with propranolol. Seven children had
pruritus, of which 3 received rifampicin because of intense
discomfort. The children received no other medication dur-
ing the study except oral vitamin supplements. Except for
discontinuing the UDCA treatment, no other modifications
were made to medical treatment during the study. No
adverse effects of UDCA treatment were observed at the
start of the study.
With the exception of 1 patient who developed jaun-
dice 3 months after UDCA treatment was stopped, we
observed no significant modification of clinical parame-
ters when UDCA treatment was discontinued. In the
patient who developed jaundice, bilirubin concentration
increased from 10 to 57 ␮mol/L; AST concentration
increased from 1.3 to 1.6 times the upper limit of normal
(⫻N), and ALT concentration increased from 1.4 to 1.9
⫻N. The jaundice disappeared within a few weeks of
reintroducing UDCA treatment and liver enzyme con-
centrations decreased to values similar to those recorded
at T0. None of the children exhibited bacterial cholangi-
tis or an increase in pruritus or hepatomegaly during the
period in which UDCA treatment was withheld.
Table 2 shows the results of biochemical tests con-
ducted before and after UDCA was discontinued. UDCA
constituted 53% (range: 19%–73%) of total serum bile
acids at T0, confirming that compliance with treatment
was good at the start of the study. UDCA constituted
⬍30% of total bile acids in only 1 patient. Between T0
and T1, AST concentration increased significantly from
1.3 ⫻N (range: 0.6 –3.4) to 1.7 ⫻N (range: 0.7– 6.0) (P ⬍
.01), ALT increased from 1.4 ⫻N (range: 0.5–5.4) to 3.0

TABLE 2 Biological Parameters Before and After UDCA Treatment Was Discontinued (n ⴝ 16)
Median (Range)
T0 at the Time of UDCA T1 at the Last Evaluation After
Discontinuation Discontinuation
Total bilirubin level, ␮mol/L 10.3 (3.4–39.3) (n ⫽ 15) 13.7 (5.1–56.4) (n ⫽ 15)
Conjugated bilirubin level, ␮mol/L 2.6 (1.7–27.2) (n ⫽ 15) 3.4 (1.7–46.2) (n ⫽ 15)
AST level, ⫻N 1.3 (0.6–3.4) (n ⫽ 16) 1.7 (0.7–6.0) (n ⫽ 16)
ALT level, ⫻N 1.4 (0.5–5.4) (n ⫽ 16) 3.0 (0.8–7.0) (n ⫽ 16)
GGT level, ⫻N 4.2 (0.5–27.4) (n ⫽ 16) 8.0 (1.8–30.2) (n ⫽ 15)
Total serum bile acid level, ␮mol/L 56 (5–370) (n ⫽ 15) 54 (2–288) (n ⫽ 14)
UDCA enrichment of serum bile acids, % of total 53 (18.8–73.0) (n ⫽ 12) 0 (0–11) (n ⫽ 14)
serum bile acid
Sum of serum cholic and chenodeoxycholic 33 (2–130) (n ⫽ 12) 53 (2–279) (n ⫽ 14)
acids, ␮mol/L
Prothrombin time, % 96 (66–100) (n ⫽ 16) 90 (67–100) (n ⫽ 15)
Factor V, % 100 (54–151) (n ⫽ 15) 84 (51–144) (n ⫽ 14)
Values are expressed as medians (minimum to maximum). ⫻N indicates multiple of the upper limit of value considered normal in this laboratory.

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 8 300

Serum cholic + chenodeoxycholic

7 a 250
6 a
a
5 200

acids, µmol/L
4 150
3
100
2
FIGURE 1 1 50
Concentrations of ALT, AST, GGT, and cholic and 0
T0 T1 T2 0
chenodeoxycholic acids at various times during T0 T1 T2
the study. ⫻N, multiple of the upper limit of value 7
35
considered normal in this laboratory. a Significant
30 6
difference between values for T1 and T0 or be- a
a a
tween values for T2 and T1 (P ⬍ .05). 25 5
a
20

AST, × N
4

15 3
10
2
5
1
0
T0 T1 T2 0
T0 T1 T2

⫻N (range: 0.8 –7.0) (P ⬍ .02), and GGT from 4.2 ⫻N
(range: 0.5–27.4) to 8.0 ⫻N (range: 1.8 –30.2) (P ⬍ .02)
(Fig 1). No other biological parameters changed signifi-
cantly, but endogenous bile acid concentration tended to
increase from 33 ␮mol/L (range: 2–130 ␮M/L) at T0 to
54 ␮mol/L (range: 2–279 ␮mol/L) at T1 (n ⫽ 11; P ⫽
.056) (Fig 1). Liver enzyme concentrations (AST, ALT,
and GGT) worsened in all but 2 patients after stopping
UDCA treatment (Fig 1). In these 2 patients, liver en-
zyme concentrations were stable at the long-term fol-
low-up (3 and 5 years after discontinuing UDCA). In
another patient, ALT and GGT concentrations increased
slightly at T1, but treatment was not reintroduced be-
cause liver enzyme levels were ⬍2 ⫻N for age. UDCA
was reintroduced in all but these 3 patients 3 to 36
months after the initial discontinuation.
Table 3 shows the results of biochemical assays con-
ducted before and after UDCA was reintroduced for the
13 children whose biological status worsened at T1. Six
months after UDCA treatment was restarted, liver en-
zyme concentrations decreased significantly from 1.7
⫻N (range: 0.9 – 6.0) at T1 to 1.3 ⫻N (range: 0.6 –3.9) at
T2 for AST (P ⬍ .01), from 3.1 ⫻N (range: 1.3–7.0) to 1.4
⫻N (range: 0.7–5.9) for ALT (P ⬍ .01), and from 10.6
⫻N (range: 2.4 –30.2) to 4.6 ⫻N (1.2–21.3) for GGT (P ⬍
.01). These biochemical parameters improved in all 13
patients for whom UDCA treatment was reintroduced
(Fig 1). Endogenous bile acid concentrations decreased
significantly from 68 ␮mol/L (range: 5–279 ␮mol/L) at
T1 to 57 ␮mol/L (range: 3–129 ␮M/L) at T2 (n ⫽ 11; P ⫽
.02) (Fig 1). Parameters that increased at T1 returned to
initial values at T2 (T2 vs T0, not significant). At T2,
UDCA constituted 47.5%(range: 6%– 62%) of total se-
rum bile acids, which did not differ significantly from the
corresponding percentage at T0. However, UDCA con-
stituted ⬍30% of total bile acids in 3 patients, in 1 of
whom UDCA constituted only 6% of total bile acids.
Serum bilirubin concentration, prothrombin time, and
factor V level did not change significantly during the
study.
DISCUSSION
This is the first prospective study, to our knowledge, to
show that UDCA improves liver function in children

TABLE 3 Biological Parameters Before and After UDCA Was Reintroduced (n ⴝ 13)
Median (Range)
T1 at the Last Evaluation After T2 6 Months After UDCA Treatment
Discontinuation Was Reinstituted
Total bilirubinemia, ␮mol/L 13.7 (5.1–56.4) (n ⫽ 12) 8.5 (2–40) (n ⫽ 12)
Conjugated bilirubinemia, ␮mol/L 2.6 (1.7–46.2) (n ⫽ 12) 3.4 (1.7–56.4) (n ⫽ 12)
AST level, ⫻N 1.7 (0.9–6.0) (n ⫽ 13) 1.3 (0.6–3.9) (n ⫽ 12)
ALT level, ⫻N 3.1 (1.3–7.0) (n ⫽ 13) 1.4 (0.7–5.9) (n ⫽ 12)
GGT level, ⫻N 10.6 (2.4–30.2) (n ⫽ 12) 4.6 (1.2–21.3) (n ⫽ 13)
Total serum bile acids, ␮mol/L 75 (5–288) (n ⫽ 11) 114 (6–198) (n ⫽ 13)
UDCA enrichment of serum bile acids, % of 0 (0–11) (n ⫽ 11) 55 (6–76) (n ⫽ 11)
total serum bile acids
Sum of serum cholic and chenodeoxycholic 68 (5–279) (n ⫽ 11) 57 (3–129) (n ⫽ 11)
acid levels, ␮mol/L
Prothrombin time, % 87.5 (67–100) (n ⫽ 13) 85 (68–100) (n ⫽ 13)
Factor V, % 80 (51–130) (n ⫽ 12) 81.5 (53–130) (n ⫽ 12)
Values are expressed as medians (minimum to maximum). ⫻N indicates multiple of the upper limit of value considered normal in this laboratory.

PEDIATRICS Volume 122, Number 6, December 2008 e1239

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after successful surgery for BA and that its biological
benefits persist for several years after treatment. Discon-
tinuation of UDCA treatment was associated with a sig-
nificant worsening of liver function (assessed by using
serum levels of AST, ALT, and GGT), but liver enzyme
levels returned to initial levels when treatment was re-
introduced. Although the increase in serum concentra-
tions of endogenous bile acids (cholic and chenodeoxy-
cholic acids) did not reach significance when treatment
was stopped, concentrations decreased significantly
when UDCA was restarted. Improvement of liver func-
tion after UDCA treatment has been reported for several
other cholestatic liver diseases of children.23 Although
our study did not include a control group, changes in
liver function after interruption and reintroduction of
the drug strongly suggest that UDCA had a beneficial
effect. Furthermore, 2 children whose liver function im-
proved when UDCA was reintroduced during the study
experienced adverse changes in liver function 1 year
after a second interruption of treatment. Treatment of 1
child was interrupted and the other did not comply with
the treatment regimen, as confirmed by a low serum
concentration of UDCA, which constituted only 20% of
serum bile acids. Liver function improved again after
UDCA treatment was restarted in these 2 patients (data
not shown). A randomized control study should be nec-
essary to definitely prove the efficiency of UDCA treat-
ment, but such a study is difficult to finalize because
biliary atresia is a rare condition, as illustrated by the
small sample of our study. Furthermore, it should be
difficult to randomize such patients to a placebo given
the benefits we found in our study and the rare adverse
effects of this drug.
We found no evidence of an UDCA effect on clinical
status except for 1 child who had a recurrence of jaun-
dice during the interruption of treatment. A link be-
tween the interruption of UDCA treatment and the re-
currence of jaundice is indicated by the absence of any
other potential cause of cholestasis (eg, bacterial cholan-
gitis), that jaundice occurred within 3 months after stop-
ping UDCA treatment, and that the patient made a rapid
recovery from jaundice when UDCA treatment was re-
started. Pruritus, which is improved by UDCA treatment
after the Kasai intervention24 as in other cholestatic dis-
eases,9 did not change at any time during our study.
However, we restarted UDCA treatment as soon as the
biological parameters worsened, which was probably be-
fore clinical signs would have been evident. As our pa-
tients did not undergo liver biopsies during the study, we
could not assess the effect of UDCA on liver histology.
Only 3 children included in this study did not have to
resume UDCA treatment within several months or
years. These patients had no associated malformations
and underwent surgery at the ages of 17, 53, and 64
days. One had portal hypertension with splenomegaly
and esophageal varices at the beginning of the study.
There were no obvious differences between these chil-
dren and the others that could explain the difference in
their progress.
We used gas chromatographic analysis of bile acids to
verify the patients’ compliance with UDCA treatment.
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To our knowledge, this method has never been used in
studies on the efficacy of UDCA treatment in pediatric
cholestatic diseases. Our results show good compliance
during the study because only 3 children had low serum
UDCA concentrations after UDCA treatment was re-
started. Because compliance is a major concern, espe-
cially in chronic diseases of childhood, we recommend
the use of this technique to monitor UDCA treatment.
During UDCA therapy, serum concentrations of en-
dogenous toxic bile acids decreased as serum UDCA
concentrations increased, which is consistent with data
from previous studies.16,25 This reflects the enrichment of
bile with UDCA, a nonhepatotoxic bile acid, and the
choleretic effect of UDCA, which increases hepatic clear-
ance of toxic endogenous bile acids and confers a cyto-
protective effect on hepatocytes and constitutes the ra-
tionale for the therapeutic use of UDCA for cholestatic
liver diseases.26,27 The rationale for the use of UDCA in
BA is also based on its immunomodulatory properties
because it decreases proliferation of and cytokine pro-
duction by mononuclear cells in vitro28 and HLA antigen
I expression on hepatocytes of patients with primary
biliary cirrhosis.29 Such immunosuppressive properties
might limit immune system-induced injury, one of the
mechanisms responsible for the obliteration of bile ducts
in BA.30 An animal study using bile duct-ligated rats
showed that UDCA limits proliferation of bile ducts and
the severity of liver disease.31
UDCA is frequently used for treatment of children
with BA because of the potential mechanisms by which
it exerts beneficial effects and its demonstrated efficacy
in several cholestatic liver diseases of adults and chil-
dren.23,27 Moreover, previous studies have indicated that
UDCA has a beneficial effect on patients with BA. Ullrich
et al. 19 first administered UDCA to 2 children in whom
the Kasai procedure had failed, causing severe growth
retardation. UDCA treatment was associated with in-
creased body weight and improved liver function. In
another study, the concentrations of serum bilirubin and
total bile acids decreased in 4 of 6 children who received
UDCA shortly after the Kasai intervention.20 However,
these 2 studies were not controlled and included few
patients. Only 1 prospective, double-blind, randomized,
controlled trial, the results of which were published only
as an abstract, indicated that in the 23 patients studied,
treatment with UDCA relieved pruritus and decreased
serum liver enzyme concentrations (AST and ALT), but
had no effect on weight gain and long-term outcome
(requirement for liver transplantation).24 Our interven-
tion study is the first, to our knowledge, to demonstrate
that UDCA treatment after the Kasai intervention results
in long-term improvement of biological status, although
clinical benefit remains to be demonstrated.
CONCLUSIONS
Children who have undergone a successful portoenter-
ostomy can live for several decades with their original
liver,6,7 but the long-term management of these patients
is not well defined. The aim of treatment of this sub-
population is to slow the progression to end-stage liver
disease and increase the interval before hepatic trans-
plantation, the last therapeutic option for nearly all pa-
tients, is necessary.4,5 Our study demonstrates that the
beneficial effects of UDCA on liver function tests persist
for several years after the Kasai intervention and sup-
ports the use of prolonged treatment for children who
have undergone successful surgery for BA. Additional
placebo-randomized studies with an external concomi-
tant review to be assured that the denial of medication
does not put the placebo group at risk are needed to
assess its effect on the long-term prognosis of BA in
children.
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PEDIATRICS Volume 122, Number 6, December 2008 e1241
Effect of Ursodeoxycholic Acid on Liver Function in Children After Successful
Surgery for Biliary Atresia
Stephanie Willot, Stephanie Uhlen, Laurent Michaud, Gilbert Briand, Michel
Bonnevalle, Rony Sfeir and Frédéric Gottrand
Pediatrics 2008;122;e1236
DOI: 10.1542/peds.2008-0986 originally published online November 24, 2008;

Updated Information & including high resolution figures, can be found at:
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References This article cites 31 articles, 0 of which you can access for free at:
http://pediatrics.aappublications.org/content/122/6/e1236#BIBL
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Effect of Ursodeoxycholic Acid on Liver Function in Children After Successful
Surgery for Biliary Atresia
Stephanie Willot, Stephanie Uhlen, Laurent Michaud, Gilbert Briand, Michel
Bonnevalle, Rony Sfeir and Frédéric Gottrand
Pediatrics 2008;122;e1236
DOI: 10.1542/peds.2008-0986 originally published online November 24, 2008;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/122/6/e1236

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
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the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
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