ORIGINAL ARTICLE
G ow h o child en wi h bilia y a esia li ing wi h na i e li e s: impac
o co icoid he apy a e po oen e os omy
Sa u Ma ia Ruuska
1,2
&Mi ja Tapani Lääpe i
3
&Ma ia Hukkinen
2,4
&Hannu Jalanko
5
&Kaija-Leena Kolho
6,7
&
Mikko P. Paka inen
2,3,4
Recei ed: 10 Oc obe 2018 /Re ised: 5 No embe 2018 /Accep ed: 27 No embe 2018 /Published online: 5 Decembe 2018
#The Au ho (s) 2019
Abs ac
We add essed g ow h o bilia y a esia (BA) pa ien s li ing wi h na i e li e s be ween ages 0–6 and e ec s o pos -su gical
co icos e oid ea men on g ow h. G ow h cha s o 28 BA pa ien s bo n in Finland be ween 1987 and 2017 we e e ospec i ely
e alua ed. Dosage and leng h o co icos e oid ea men and hyd oco isone subs i u ion we e e iewed. A bi h, BA pa ien s
we e sho e (median heigh −0.6 (in e qua ile ange (IQR) −1.3 o −0.1) SDS, n=28,P< 0.001) han gene al popula ion.
Heigh emained s able du ing ea ly childhood (median heigh −0.6 (IQR −1.4 o 0.1) SDS o gi ls and −0.4 (IQR −1.6 o 0.2)
SDS o boys a 6 yea s o age). Pa ien s we e o no mal heigh adjus ed weigh a 6 yea s wi h a median age and sex-adjus ed
body mass index (ISO-BMI) o 20.9 (IQR 19.3 o 25.0) o gi ls and 22.1 (IQR 20.7 o 25.6) o boys. Highe (≥50 mg/kg)
cumula i e pos -po oen e os omy p ednisolone dosage esul ed in 0.18 SDS lowe heigh pe ea men week (β−0.18, SE 0.04,
P< 0.001) compa ed o lowe dosage (< 50 mg/kg).
Conclusion: BA pa ien s g ow no mally du ing ea ly childhood. As high pos ope a i e co icos e oid dosage has a sho - e m
nega i e e ec on heigh , e y high dosages should be a oided.
Wha Is Known:
•G ow h o bilia y a esia pa ien s has mos ly been shown o be wi hin no mal limi s
•Co icos e oids may dec ease g ow h a e
Wha Is New:
•Bilia y a esia pa ien s su i ing wi h hei na i e li e s a e sho e han gene al popula ion and hei mid-pa en al a ge heigh a bi h
•A high (> 50 mg/kg) cumula i e p ednisolone dosage has a nega i e ansi o y impac on heigh gain a e po oen e os omy
Keywo ds Age and sex-adjus ed body mass index (ISO-BMI) .Bilia y a esia (BA) .Co icos e oids .Po oen e os omy
Communica ed by Pe e de Win e
*Sa u Ma ia Ruuska
sa u. uuska@hus. i
Mi ja Tapani Lääpe i
mi ja@laape i.com
Ma ia Hukkinen
ma ia.hukkinen@hus. i
Hannu Jalanko
hannu.jalanko@hus. i
Kaija-Leena Kolho
kaija-leena.kolho@helsinki. i
Mikko P. Paka inen
mikko.paka inen@hus. i
1
Depa men o Gas oen e ology, Child en’s Hospi al, Helsinki
Uni e si y Hospi al, PL 347, 00029 HUS Helsinki, Finland
2
Pedia ic Li e and Gu Resea ch G oup, Child en’s Hospi al,
Helsinki Uni e si y Hospi al, Helsinki, Finland
3
Pedia ic Resea ch Cen e , Child en’s Hospi al, Helsinki Uni e si y
Hospi al, Helsinki, Finland
4
Sec ion o Pedia ic Su ge y, Child en’sHospi al,Helsinki
Uni e si y Hospi al, Helsinki, Finland
5
Depa men o Pedia ic Neph ology and T ansplan a ion, Child en’s
Hospi al, Helsinki Uni e si y Hospi al, Helsinki, Finland
6
Uni e si y o Tampe e, Tampe e, Finland
7
Tampe e Uni e si y Hospi al, Tampe e, Finland
Eu opean Jou nal o Pedia ics (2019) 178:341–349
h ps://doi.o g/10.1007/s00431-018-3302-z
Abb e ia ions
BA Bilia y a esia
BASM Bilia y a esia splenic mal o ma ion
COJ Clea ance o jaundice
DW% Weigh - o -leng h
IQR In e qua ile ange
ISO-BMI Age- and sex-adjus ed body mass index
LT Li e ansplan a ion
MPH Mid-pa en al a ge heigh
PE Po oen e os omy
SDS S anda d de ia ion sco es
In oduc ion
Bilia y a esia (BA) is an idiopa hic ib o-obs uc i e
cholangiopa hy mani es ing in in ancy [20].The incidence
o BA is a ied be ween 1:8000 and 1:10000 epo ed in
Asia o 1:17000–1:20000 in No he n Eu ope [26–28].
Un ea ed, obs uc ion o in a- and ex ahepa ic bilia y acks
leads o ib osis, li e ailu e, and dea h in he i s 2 yea s. The
cu en i s -line su gical ea men is po oen e os omy (PE).
P o ided PE es o es adequa e bile low, be ween 23% and
44% o pa ien s su i e wi h na i e li e s un il he age o 20
[10,29,41]. Li e ansplan a ion (LT) emains a second-line
ea men op ion and BA is he mos common indica ion o
childhood LTs [20,30].
Following PE, commonly used adjunc pos ope a i e man-
agemen includes u sodeoxycholic acid, p ophylac ic an ibi-
o ic ea men , and nu i ional managemen [11,47,49].
Co icos e oids may imp o e clea ance o jaundice (COJ)
a es bu po en ial side e ec s include an ele a ed isk o
in ec ions, gas oin es inal bleeding, os eopo osis, and poo
g ow h [5,7,9]. G ow h pa e ns o pa ien s su i ing wi h
hei na i eli e sha e a elybeen epo edon,andda aon he
e ec pos -PE co icos e oids ha e on g ow h a e e y limi ed
[1,5,12,34]. The aim o his s udy was o cha ac e ize g ow h
o BA pa ien s su i ing wi h hei na i e li e s be ween he
ages 0–6. Fu he mo e, we measu ed he e ec o pos -PE
co icos e oids on g ow h.
Me hods
Pa ien s
We included e m BA pa ien s bo n in Finland be ween
1987 and 2017 who had no malized hei bili ubin <
20 μmol/l a e PE, we e a leas 4 mon hs old, and we e
li ing wi h hei na i e li e s as o 31s o Decembe
2017. Da a on ges a ional age, bi h heigh , and weigh ,
associa ed congeni al mal o ma ions, BA- ype [36], age a
su ge y, se ial heigh and weigh measu emen s,
co icos e oid ea men , and subsequen hyd oco isone
subs i u ion we e e ospec i ely collec ed om medical
eco ds. Te m in an was de ined as weigh a o abo e
2500 g and ges a ional age be ween 37 and 42 weeks a
bi h. Bilia y a esia splenic mal o ma ion (BASM) was
de ined as p esence o poly- o asplenia [8]. Clea ance
o jaundice was de ined as se um o al bili ubin <
20 μmol/L.
G ow h da a
Heigh and weigh a bi h as well as a 3, 6, 9, 12, 15, 18,
21, and 24 mon hs and a yea ly in e als be ween 2 and
20 yea s o age we e e ospec i ely collec ed om med-
ical eco ds. Heigh and weigh a PE and a 1, 2, 3, 4, 5,
6, 9, 12, 15, 18, 21, and 24 mon hs a e PE we e also
e ie ed om medical eco ds. Fo he i s yea , mea-
su emen s pe o med wi hin a ± 4-week pe iod o he ex-
ac ime poin we e accep ed bu o g ow h da a a e
po oen e os omy, o he i s 12 mon hs, he nea es
a ailable measu emen was accep ed i i was wi hin a ±
2-week pe iod o he exac ime poin . A e 12 mon hs,
measu emen s wi hin a ± 6-week pe iod o he excep ime
poin we e accep ed.
Heigh was analyzed as s anda dde ia ionsco es
(SDS) om he mean o age- and sex-adjus ed na ional
alues [39]. No mal heigh was de ined as heigh SDS
be ween −2.0 and 2.0. Mid-pa en al a ge heigh SDS
we e calcula ed acco ding o he equa ions: 0.791 × mean
pa en al heigh SDS −0.147 o gi ls and 0.886 × mean
pa en al heigh SDS –0.071 o boys [40]. Be ween bi h
and 2 yea s o age, ela i e weigh was analyzed as
weigh - o -leng h, i.e., he pe cen age de ia ion o weigh
om he median weigh o leng h and sex (DW%) [39,
44]. A e he age o 2, ela i e weigh was analyzed wi h
age- and sex-adjus ed body mass index (ISO-BMI) [39].
Du ing he i s 2 yea s, unde weigh was de ined as
DW% < −20.0, no mal weigh as DW% be ween −20.0
and + 20.0 and o e weigh as DW% > 20.0 [39,44]. Fo
ela i e weigh be ween ages 2–6, he ollowing ISO-BMI
ca ego ies we e used: unde weigh (< 17 kg/m
2
), no mal
weigh (17–25 kg/m
2
), o e weigh (> 25 kg/ m
2
), and
obesi y (> 30 kg/m
2
)[39]. While calcula ing changes in
ela i e weigh a e po oen e os omy, ela i e weigh
was analyzed as weigh - o -leng h o consis ency. The
mos ecen ly published na ional e e ence da a was used
o calcula ion o SDS o weigh and leng h [39].
Co icos e oid ea men
Cumula i e dosage o glucoco icoid ea men a e PE,
he leng h and dosage o subsequen hyd oco isone sub-
s i u ion egimen, and measu ed se um co isol alues
342 Eu J Pedia (2019) 178:341–349
a e co icos e oid ea men we e e iewed om pa ien
eco ds. Co icos e oid dosage was con e ed o equi alen s
o p ednisolone, and o al cumula i e dosage o p ednisolone
(mg) pe weigh (kg) was calcula ed. In con e ing, 5 mg o
p ednisolone was conside ed o be equi alen o 5 mg o p ed-
nisone, 20 mg o hyd oco isone, 670 μg o dexame hasone,
and 4 mg o me hylp ednisolone [31]. A high o al p edniso-
lone dosage was conside ed o be ≥50 mg/kg [9]. All possible
glucoco icoid usages ela ed o un ela ed o BA a e he ini-
ial ea men pe iod we e eco ded. The ela ionship o cumu-
la i e glucoco icoid dosage o changes in ela i e heigh and
weigh 2 yea s a e PE we e analyzed. While analyzing he
impac co icos e oids had on g ow h, possible impac was
hypo hesized o s a a he beginning o medica ion and con-
inue un il 24 mon hs. P io o na ional cen aliza ion o BA
ea men in 2005 [26], a ied pos ope a i e managemen p o-
ocols we e used wi h a median cumula i e pos su gical co -
icos e oid dosage co esponding o 50 mg/kg (IQR 26 o 62)
o p ednisolone. A e cen aliza ion, adju an co icos e oid
he apy a e PE has been used [22]. Be ween 2005 and 2014,
co icos e oid he apy wi h o al dexame hasone co esponded
o cumula i e dosage o 45 mg/kg o p ednisolone; since
2015, he dosage has co esponded o 75 mg/kg o
p ednisolone.
S a is ical me hods
Values a e exp essed as medians wi h in e qua ile ange
(IQR) unless o he wise s a ed. Wilcoxon signed- ank es
was used o compa e ma ched g oups. G ow h o pa ien s
was modeled using linea mixed models [4]. Models in-
cluded andom e ec o pa icipan s on all ime e ms.
Analyses we e ca ied ou in R e sion 3.4.1 using pack-
ages lme4 and lme Tes [25,38]. Deg ees o eedom
we e es ima ed using Sa e hwai e app oxima ions. The
s a is ically signi ican le el was se o P<0.05.
Resul s
Pa ien cha ac e is ics
Du ing he s udy pe iod, 96 pa ien s we e diagnosed wi h
BA in Finland. O hese, 30 pa ien s had died, 28 we e
ali e wi h a li e ansplan (median age a ansplan a ion
1.45 (0.84 o 2.51) yea s), 3 we e bo n p e e m and 1 had
a bi hweigh < 2500 g. Thus, 34 pa ien s ul illed he
ini ial inclusion c i e ia. Six pa ien s we e excluded as
ollows: wo because o missing heigh measu emen s a
bi h and ou because bo h pa en s we e non-Eu opean.
AsshowninTable1, median ges a ional age was
39 weeks. Mos pa ien s we e diagnosed wi h BA ype 3
and PE was pe o med a median age 63 days. Median
ollow-up age was 8.1 yea s and pa ien s had well-
p ese ed li e unc ion.
Heigh gain be ween 0 and 6 yea s
A bi h, BA pa ien s we e sho e (median heigh −0.6 (−1.3
o −0.1) SDS o all pa ien s, n=28,P< 0.001) han he gen-
e al popula ion. Median heigh SDS o pa ien s wi h mid-
pa en al a ge heigh (MPH) da a (n= 20) was −0.2 (−1.2
o 0.2), which was 0.1 SDS below hei median MPH o −
0.1 (−0.4 o0.4)SDS(mediandi e ence0.3,n= 20,
P<0.05).
G ow h a e appea ed o slow down du ing he i s
3 mon hs, as median heigh o all pa ien s a 3 mon hs was
−1.70 (−2.3 o −1.1) SDS. Change in g ow h a e was mo e
d as ic o boys (n= 13); hei median SDS changed om −
0.6 (−1.5 o −0.1) a bi h o −1.8 (−2.5 o −0.8) a 3 mon hs
while gi ls’(n= 15) median SDS changed om −0.7 (−0.7 o
0.4) SDS o −1.4 (−1.8 o −1.1) SDS (Fig. 1). A 6 mon hs,
boys’g ow h a e accele a ed as median heigh o all pa ien s
was −1.2 (−2.2 o −0.7) SDS, −1.2 (−2.1 o −0.5) SDS o
boys and −1.3 (−2.3 o −0.7) SDS o gi ls. Be ween 6 and
24 mon hs, g ow h a e was s able (Fig. 1). A 2 yea s, pa ien s
emained sho e (median heigh o all pa ien s −0.8 (−1.2 o
−0.1) SDS) han he gene al popula ion. A 2 yea s, 11/13
(85%) o he pa ien s had heigh SDS below MPH (median
di e ence = 0.8, n=13,P<0.05).
Heigh gain was s able be ween ages 2–6. Gi ls’heigh was
unal e ed wi h median heigh a −0.6 (−1.2 o −0.1 and −1.4
o 0.1 a 2 and 6 yea s, espec i ely) SDS while boys’median
heigh changed om −0.9 (−1.3 o 0.0) SDS o −0.4 (−1.6 o
0.2) SDS.
Weigh gain be ween 0 and 6 yea s
A bi h, pa ien s we e o no mal weigh wi h median 0.0 (−
5.0 o 5.5) DW% o all, 2.0 (−5.0 o 6.0) DW% o gi ls and
0.0 (−6.0 o 4.5) DW% o boys. Du ing he i s 2 yea s, bo h
gende s emained o no mal weigh wi h median o 2.5 (−1.0
o 10.5) DW% o all, −1.0 (−3.5 o 4.0) DW% o gi ls and
8.0 (2.5 o 17.5) DW% o boys a 2 yea s o age (Fig. 1).
When analyzing wi h ISO-BMI, a 2 yea s, o e all me-
dian ISO-BMI was 24.1 (20.5 o 28.8), i.e., on he uppe
ma gin o no mal ange. The e was a dis inc di e ence
be ween gende s; gi ls we e o no mal weigh wi h medi-
an o 21.1 (19.7 o 23.3) ISO-BMI while boys we e o e -
weigh wi h a median o 25.9 (24.1 o 32.3) ISO-BMI
(Fig. 2).Gi ls’weigh emained cons an be ween ages
2–6 yea s wi h a median o 20.9 (19.3 o 25.0) ISO-
BMI a 6 yea s. Boys’weigh dec eased sligh ly wi h −
1.06 (β−1.06, SE 0.33, P< 0.05) ISO-BMI yea ly wi h
median ISO-BMI a 22.1 (20.7 o 25.6) a 6 yea s (Fig. 2).
Eu J Pedia (2019) 178:341–349 343
Pos ope a i e co icos e oid ea men and g ow h
Comple e da a o pos su gical co icos e oid ea men was
a ailable o 24 ou o 28 pa ien s, including 3 pa ien s no
ea ed wi h co icos e oids. Co icos e oid ea men s a ed a
median 5 ( ange 4–17) days a e PE a median age o 70
( ange 18–167) days. The median leng h o co icos e oid-
ea men was 18.5 ( ange 0–49) days. Six een pa ien s e-
cei ed hyd oco isone subs i u ion. To al median cumula i e
co icos e oid dosage was 277.6 (186.6 o 374.2) mg and 63.6
(47.7 o 74.6) mg/kg o p ednisolone excluding hyd oco i-
sone subs i u ion. Median hyd oco isone dosage du ing he
i s 30 days o subs i u ion was 8.2 ( ange 5.0–21.2) mg/m
2
/
day and median ea men leng h was 37 ( ange 12–133) days.
Se um co isol alues we e supp essed a e glucoco icoid
ea men in 12 ou o 19 pa ien s (63%) wi h measu ed alues.
A PE (median age 65 (IQR 26 o 90) days), pa ien s we e
1.51 (β−1.51, SE 0.19, P< 0.001) SDS sho e han he
gene al popula ion. A g ow h model o cumula i e p ednis-
olone dosage showed 0.16 (β−0.16, SE 0.04, P<0.001)SDS
dec ease in heigh o each 100 mg o p ednisolone. In a
mixed model, he e was 0.18 (β−0.18, SE 0.04, P<0.001)
SDS dec ease in heigh o each 100 mg o p ednisolone while
hyd oco isone subs i u ion caused ain 0.07 (β0.07, SE 0.02,
P< 0.05) SDS inc ease in heigh pe ea men week. A
weigh -adjus ed dosage model showed nega i e e ec on
heigh wi h 0.25 (β−0.25, SE 0.05, P< 0.001) SDS dec ease
o each 100 mg o p ednisolone pe ea men week. In a
mixed model, weigh -adjus ed dosage o p ednisolone dem-
ons a ed 0.27 (β−0.27, SE 0.05, P< 0.001) SDS dec ease
o each 100 mg o p ednisolone pe ea men week while
hyd oco isone subs i u ion caused 0.07 (β0.07, SE 0.02,
P< 0.01) SDS inc ease in heigh pe week. A highe o al
co icos e oid dosage (> 50 mg/kg) esul ed in 0.18 (β−
0.18, SE 0.04, P< 0.001) SDS lowe heigh pe ea men
week compa ed o lowe dosage. The e ec emained in a
Table 1 Pa ien cha ac e is ics
All pa ien s Pa ien s wi h glucoco icoid da a
Numbe o pa ien s 28 24
Ges a ional age, wk, median (IQR) 39 (38–40) 39 (38–40)
Females, n(%) 15(54) 12(50)
Bi h weigh , median (IQR)
kg 3.340 (3.081–3.669) 3.363 (3.081–3.669)
%0.0(−5.0–5.5) 0.0 (−6.5–5.5)
Bi h heigh , median (IQR)
cm 50.0 (48.6–51.0) 50.0 (49.0–51.0)
SD −0.6 (−2.2–(−0.1)) −0.6 (−1.0–0.3)
Bilia y a esia ype n(%)
1 0 (0.0) 0 (0.0)
2 2 (7.1) 0 (0.0)
3 26 (92.9) 24 (100)
Bilia y a esia splenic mal o ma ion, n(%) 3 (11) 3 (13)
Any o he anomaly, n(%) 10 (36) 8 (33)
Age a po oen e os omy (PE), days, median (IQR) 63 (24–83) 65 (26–90)
Time o clea ance o jaundice, mon hs, median (IQR) 2 (1–3) 2.5 (1–3.8)
Diagnosed wi h po al hype ension, n(%) 12 (43) 12 (50)
Age a las ollow-up, yea s, median ( ange) 8.1 (0.3–19.7) 7.8 (0.3–19.7)
Biochemical ma ke s a las ollow-up:
Bili ubin, μmol/L, median (IQR) 8.5 (7–14) 8.5 (5.5–14.8)
Conjuga ed bili ubin, μmol/L, median (IQR) 4 (3–7) 4.0 (3–7.8)
Alanine amino ans e ase, U/L, median (IQR) 40 (19–76) 55 (27–77)
Aspa a e amino ans e ase, U/L, median (IQR) 54 (34–90) 57 (42–100)
Glu amyl ans e ase, U/L, median (IQR) 48 (21–100) 65 (27–105)
Albumin, g/L, median (IQR) 38 (32–40) 37 (32–40)
Th omboplas in ime %, median (IQR) 87 (73–100) 87 (73–105)
Th ombocy es, × 10
9
/L, median (IQR) 174 (79–268) 155 (71–268)
IQR in e qua ile ange, PE = po oen e os omy. Bilia y a esia ypes as de ined by Ohi e al. [18], po al hype ension as de ined by Shneide e al. [42]
344 Eu J Pedia (2019) 178:341–349
a. b. c.
d. e. .
Fig. 1 G ow h o BA pa ien s du ing i s 2 yea s, pos na al age, 3-mon h
in e als. aHeigh SDS o all pa ien s. bHeigh SDS o gi ls. cHeigh
SDS o boys. dWeigh - o -leng h (DW%) o all pa ien s. eWeigh - o -
leng h (DW%) o gi ls. Weigh - o -leng h o boys (DW%). G ay a ea
be ween dashed lines: no mal weigh wi h DW%. Da a a e p esen ed wi h
median and in e qua ile ange (pe cen ile 25–75). SDS, s anda d de ia-
ion sco es om he mean o age- and sex-adjus ed alue; DW%, pe -
cen age de ia ion o weigh om median weigh o leng h and sex;
MPH, mid-pa en al a ge heigh
Fig. 2 G ow h o BA pa ien s be ween 2 o 6 yea s wi h yea ly in e als.
aHeigh SDS o all pa ien s. bHeigh SDS o gi ls. cHeigh SDS o
boys. dWeigh ISO-BMI o all pa ien s. eWeigh ISO-BMI o gi ls. .
Weigh ISO-BMI o boys. G ay a ea be ween dashed lines: no mal
weigh wi h ISO-BMI. Da a a e p esen ed wi h median and in e qua ile
ange (pe cen ile 25–75). SDS, s anda d de ia ion sco es om he mean
o age- and sex-adjus ed alue; ISO-BMI, age- and sex-adjus ed body
mass index
Eu J Pedia (2019) 178:341–349 345

model including highe co icos e oid dosage (β−0.21, SE
0.04, P< 0.001) and hyd oco isone subs i u ion (β−0.05,
SE 0.02, P< 0.01). Supp ession o co isol p oduc ion caused
1.37 (β−1.37, SE 0.55, P< 0.05) SDS dec ease pe week in
heigh compa ed o unsupp essed pa ien s (Table 2).
Pa ien s we e o no mal weigh wi h −0.44 (β−0.44, SE
1.53, P0.776) DW% a ime o po oen e os omy. A g ow h
model o o al cumula i e p ednisolone showed no e ec on
weigh , no did a g ow h model combining cumula i e p ednis-
olone and hyd oco isone subs i u ion (Table 2). A g ow h
model wi h weigh -adjus ed co icos e oid dosage showed no
e ec o p ednisolone on weigh no did a model combining
weigh -adjus ed dosage and hyd oco isone subs i u ion
(Table 2).A highe o al co icos e oid dosage caused 1.12 (β
1.12, SE 0.36, P< 0.01) DW% inc ease in weigh pe ea men
week compa ed o lowe dosage, he e ec emained (β0.87,
SE 0.38, P< 0.05) in a mixed model including hyd oco isone
subs i u ion (β0.32, SE 0.15, P< 0.05). Supp ession o co isol
p oduc ion had no e ec (Table 2).
Discussion
We desc ibe g ow h pa e ns o e m BA pa ien s li ing wi h
na i e li e s om bi h un il ea ly childhood. We ound ha
hey a e sho e han gene al popula ion and hei mid-pa en al
a ge heigh a bi h. Thei heigh gain emains cons an du -
ing in ancy and ea ly childhood. BA pa ien s we e bo n o
no mal weigh and emained o no mal weigh du ing i s
2 yea s. Gi ls emained o no mal weigh be ween 2 and
6 yea s whe eas boys’weigh , while analyzed wi h ISO-
BMI, slimmed down om o e weigh o no mal weigh . A
high cumula i e co icos e oid ea men dosage had a ma ked
empo a y nega i e impac on heigh gain.
Table 2 Linea mixed models’ esul s o heigh and weigh o
di e en pa ame e s. The es ima es a e o ei he changes in
s anda dized heigh (SD) o ISO-BMI. Models o (1.) ime only, (2.) ime
and cumula i e p ednisolone, (3a.) ime and weigh -adjus ed
p ednisolone, (4a.) ime and high p ednisolone dosage, and (5.) ime
and co isol supp ession. The (b) models ex ended he (a) models wi h
hyd oco isone subs i u ion
Models o heigh
a
: Pa ame e Es ima e, βS anda d e o , SE P
1. In e cep −1.51 0.19 <0.001
Time, 1 mon h 0.05 0.01 <0.001
2 a. Cumula i e p ednisolone pe 100 mg −0.16 0.04 <0.001
b. Cumula i e p ednisolone pe 100 mg −0.18 0.04 <0.001
Hyd oco isone subs i u ion pe week 0.07 0.02 0.007
3 a. Weigh -adjus ed p ednisolone pe
100 mg pe week
−0.25 0.05 <0.001
b. Weigh -adjus ed p ednisolone pe
100 mg pe week
−0.27 0.05 <0.001
Hyd oco isone subs i u ion pe week 0.07 0.02 0.004
4a. Highdosagepe week −0.18 0.04 <0.001
b. High dosage pe week −0.21 0.04 <0.001
Hyd oco isone subs i u ion pe week −0.05 0.02 0.006
5. Co isol supp ession pe week −1.37 0.55 0.014
Models o weigh
a
:
1. In e cep −0.44 1.53 0.776
Time, 1 mon h 0.31 0.11 0.011
2 a. Cumula i e p ednisolone pe 100 mg 0.58 0.40 0.144
b. Cumula i e p ednisolone pe 100 mg 0.47 0.42 0.263
Hyd oco isone subs i u ion pe week 0.15 0.17 0.384
3 a. Weigh -adjus ed p ednisolone pe
100 mg pe week
0.32 0.47 0.496
b. Weigh -adjus ed p ednisolone pe
100 mg pe week
0.16 0.49 0.751
Hyd oco isone subs i u ion pe week 0.19 0.17 0.259
4 a. High dosage pe week 1.12 0.36 0.002
b. High dosage pe week 0.87 0.38 0.024
Hyd oco isone subs i u ion pe week 0.32 0.15 0.033
5. Co isol supp ession pe weeks 2.43 5.15 0.638
a
All models adjus ed o ollow-up ime, excep o he i s (1.) ime only uni a ia e model
346 Eu J Pedia (2019) 178:341–349
Resul s on weigh a ied a 2 yea s o age depending
whe he ela i e weigh was analyzed wi h DW% o ISO-
BMI; when analyzed wi h DW%, bo h gi ls and boys we e
o no mal weigh whe eas boys we e o e weigh when ana-
lyzed wi h ISO-BMI. This disc epancy likely s ems om he
ac ha he e is no known co ela ion o DW% and ISO-BMI
be ween ages 0 o 2. Single USA-based s udy comp ising
4348 child en ound poo co ela ion be ween weigh - o -
heigh and BMI- o -age be ween ages 2–5. In line wi h ou
indings, high pe cen age (63.4%) o child en had lowe
weigh - o -heigh pe cen ile han BMI- o -age pe cen ile a
he same age [16].
Pa ien s in ou s udy a e sho e han gene al popula ion
and hei mid-pa en al a ge heigh a bi h. BA associa ed
wi h cy omegalo i us in ec ion has been desc ibed o ha e
wo se clinical ou come wi h inc eased mo ali y [50], al-
hough a p e ious s udy om Sweden yielded equal clinical
esul s independen o cy omegalo i us s a us [15].
Symp oma ic congeni al cy omegalo i us in ec ion may man-
i es as s un ed g ow h especially a ec ing bi h weigh , how-
e e , he as majo i y o child en wi h congeni al cy omega-
lo i us in ec ion a e asymp oma ic [6,13,33]. As none o he
pa ien s in ou s udy we e diagnosed wi h cy omegalo i us
in ec ion, i is unlikely ha his i us caused he diminished
bi h heigh .
Published da a assessing g ow h o nonjaundiced child en
wi h BA li ing wi h na i e li e s in ea ly childhood a e spa se.
Sokol e al. [43] ound dep essed heigh and weigh z-sco es
bu no mal weigh - o -heigh z-sco es o 32 BA pa ien s in
ea ly childhood. Howe e , as 21 ou o 32 pa ien s in hei
coho had signs o ci hosis al hough pa ien s we e clinically
s able, i is likely ha ou s udy g oup consis s o heal hie
pa ien s. Ka e e al. [23] epo ed no mal heigh sco es o
he majo i y o 30 pa ien s su i ing a leas 10 yea s a e
po oen e os omy bu hei esul s also included ansplan ed
pa ien s. Thi y- i e ou o 38 nonjaundiced BA pa ien s su -
i ing wi h na i e li e s a leas 10 yea s we e epo ed o
ha e no mal g ow h by Valaye [46]. Hadziće al. [19] ound
no mal heigh and weigh z-sco es a ollow-up in 28 BA
pa ien s li ing wi h na i e li e s, hese pa ien s we e also con-
side able olde adolescen s compa ed o ou coho (median
age 13.4 ( ange 10.2–22.2) yea s s 8.1 ( ange 0.3–19.7) yea s
in ou coho ). Ng e al. [34] epo ed no mal median heigh
and weigh z-sco es o 219 BA pa ien s (median age 9.7
( ange 5.1–17.9)) li ing wi h na i e li e s a leas 5 yea s a e
po oen e os omy. Simila ly o ou indings, A ay e al. [2]
desc ibed dec eased heigh - o -age and no mal weigh - o -age
in a g oup o 10 BA pa ien s li ing wi h na i e li e s be ween
ages 1 o 12. In e es ingly, hey ound BMI and weigh - o -age
z-sco es in e sely co ela ed wi h age [2]. In ou s udy, boys
weigh dec eased be ween ages 2 o 6. While i is possible o
a gue ha lowe ela i e weigh migh e lec poo e nu i ion-
al s a us, pa ien s in ou s udy demons a ed unal e ed heigh
gain and we e o no mal weigh a he end o ollow-up
sugges ing adequa e ene gy and p o ein in ake o sus ain
g ow h.
Pos na al co icos e oids ha e been used o p e en ion
and ea men o ch onic lung disease in p e e m in an s
since 1980s [3]. In p e e m in an s, sys emic co icos e-
oidsha ebeenshown osupp essg ow h[
45,48]. To
ou bes knowledge, he e is only one p io s udy on he
e ec o pos ope a i e co icos e oid ea men on g ow h
o BA pa ien s [1]. The ole o pos su gical co icos e oids
emains polemic as p e ious s udies om Asia [24,32],
Eu ope [9], and he USA [14] ha e shown highe clea -
ance o jaundice a es o pa ien s ea ed wi h co icos e-
oids, bu his bene icial inding was no ecip oca ed in a
la ge No h-Ame ican placebo-con olled ial [5]. The
START ial [1,5] ecen ly epo ed lowe han no ms z-
sco es o leng h om po oen e os omy (69 pa ien s) un-
il 24 mon hs o age (35 pa ien s) and o weigh om
po oen e os omy (70 pa ien s) un il 18 mon hs o age
(42 pa ien s) o BA pa ien s ea ed wi h pos -su gical
co icos e oids (cumula i e p ednisolone dosage 116 mg/kg).
They also ound signi ican di e ence be ween leng h z-sco es
a 1, 2, and 3 mon hs a e po oen e os omy be ween pa ien
g oups ea ed wi h co icos e oids o placebo (70 pa ien s in
each g oup) [1]. In line wi h hese indings, in ou s udy, a
highe cumula i e co icos e oid dosage (> 50 mg/kg) nega-
i ely associa ed wi h g ow h by empo a ily signi ican ly
slowing heigh gain. In con as o START ial, we did no
obse e a long- e m nega i e impac o co icos e oids on
weigh o heigh ; his is mos likely due o he lowe dosage
o co icos e oids used in ou coho . In ou coho , g ow h
accele a ed be ween 3 and 6 mon hs o age (median age a
po oen e os omy o all pa ien s was 63 days) and heigh gain
was s able a e ha . Al hough in choles a ic li e disease in
ea ly childhood he e a e mul iple ac o s, such as changes in
g ow h ho mone unc ion [17,21], inadequa e eso p ion o
nu i ion [35], and ele a ed ene gy consump ion [18,37]pos-
sibly a ec ing g ow h; he impac o co icos e oids was clea -
ly obse able in ou coho o child en wi h well-p ese ed
li e unc ion.
Ou s udy has some limi a ions. Because da a we e collec -
ed e ospec i ely, we we e unable o cap u e comple e g ow h
da a o all pa ien s a all ime poin s. Secondly, pa ien s’nu-
i ional s a us be o e PE and ene gy and p o ein in ake du ing
ollow-up could no be assessed eliably.
In conclusion, we ound ha BA pa ien s su i ing wi h
hei na i e li e s a e sho e han hei backg ound popula ion
a bi h. Thei heigh gain s ays s able du ing ea ly childhood.
High pos -PE co icos e oid ea men dosage has a nega i e
impac on heigh gain and an obse able posi i e impac on
weigh gain compa ed o lowe dosage, bu hese e ec s a e o
sho du a ion. Howe e , as he e a e con lic ing esul s ega d-
ing he bene icial e ec s o pos su gical co icos e oid
Eu J Pedia (2019) 178:341–349 347
ea men o BA pa ien s, i is wise o minimize he possible
isks o ea men and o a oid e y high co icos e oid
dosages.
Au ho s’con ibu ions Sa u Ruuska: acqui ed and analyzed he da a,
d a ed his manusc ip , and ag eed on he inal e sion o his manusc ip .
Mi ja Lääpe i: un s a is ical analysis o he s udy da a oge he wi h
Sa u Ruuska and ag eed on he inal e sion o his manusc ip .
Ma ia Hukkinen: e ised he manusc ip c i ically and ag eed on he
inal e sion o his manusc ip .
Hannu Jalanko: pa icipa ed on he design o his s udy, e ised he
manusc ip c i ically, and ag eed on he inal e sion o his manusc ip .
Kaija-Leena Kolho: designed he s udy, c i ically e ised his manu-
sc ip , and ag eed on he inal e sion o his manusc ip .
Mikko P Paka inen: designed he s udy, p o ided unding o he s udy,
c i ically e ised his manusc ip , and ag eed on he inal e sion o his
manusc ip .
Funding Open access unding p o ided by Uni e si y o Helsinki includ-
ing Helsinki Uni e si y Cen al Hospi al. This s udy was suppo ed wi h
esea ch g an s by he Sig id Jusélius Founda ion, he Finnish Pedia ic
Resea ch Founda ion, and he Helsinki Uni e si y Cen al Hospi al G an .
Compliance wi h e hical s anda ds
Con lic o in e es The au ho s decla e ha hey ha e no con lic o
in e es .
E hical app o al This s udy was app o ed by he E hical Commi ee o
Helsinki Uni e si y Hospi al and in acco dance wi h he 1964 Helsinki
decla a ion and i s la e amendmen s o compa able e hical s anda ds.
In o med consen Fo his ype o s udy o mal consen is no equi ed.
Open Access This a icle is dis ibu ed unde he e ms o he C ea i e
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C ea i e Commons license, and indica e i changes we e made.
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dic ional claims in published maps and ins i u ional a ilia ions.
Re e ences
1. Alonso EM, Ye W, Haw ho ne K e al (2018) Impac o s e oid
he apy on ea ly g ow h in in an s wi h bilia y a esia: he mul icen-
e s e oids in bilia y a esia andomized ial. J Pedia . h ps://doi.
o g/10.1016/j.jpeds.2018.07.002
2. A ay JL, Zemel BS, Gallaghe PR, Ro ne AJ, Mulbe g AE,
S allings VA, Habe BA (2005) Body composi ion o child en aged
1 o 12 yea s wi h bilia y a esia o Alagille synd ome. J Pedia
Gas oen e ol Nu 40:146–150. h ps://doi.o g/10.1097/00005176-
200502000-00012
3. Bassle D, an den Anke J (2017) Inhaled d ugs and sys emic
co icos e oids o b onchopulmona y dysplasia. Pedia Clin N
Am 64:1355–1367. h ps://doi.o g/10.1016/j.pcl.2017.08.012
4. Ba es D, Maechle M, Bolke B, Walke S (2015) Fi ing linea
mixed-e ec s models using lme4. J S a So w 67:1–48. h ps://
doi.o g/10.18637/jss. 067.i01
5. Beze a JA, Spino C, Magee JC, Shneide BL, Rosen hal P, Wang
KS, E lichman J, Habe B, He el PM, Ka pen SJ, Ke ka N,
Loomes KM, Molles on JP, Mu ay KF, Rome o R, Schwa z KB,
Shephe d R, Suchy FJ, Tu melle YP, Whi ing on PF, Moo e J,
She ke AH, Robuck PR, Sokol RJ, Childhood Li e Disease
Resea ch and Educa ion Ne wo k (ChiLDREN) (2014) Use o co -
icos e oids a e hepa opo oen e os omy o bile d ainage in in-
an s wi h bilia y a esia: he START andomized clinical ial.
JAMA 311:1750–1759. h ps://doi.o g/10.1001/jama.2014.2623
6. Boppana SB, Ross SA, Fowle KB (2013) Congeni al cy omegalo-
i us in ec ion: clinical ou come. Clin In ec Dis 57:178–181.
h ps://doi.o g/10.1093/cid/ci 629
7. Chen Y, Nah SA, Chiang L, K ishnaswamy G, Low Y (2015)
Pos ope a i e s e oid he apy o bilia y a esia: sys ema ic e iew
and me a-analysis. J Pedia Su g 50:1590–1594. h ps://doi.o g/10.
1016/j.jpedsu g.2015.05.016
8. Da enpo M, Tizza d SA, Unde hill J, Mieli-Ve gani G, Po mann
B, HadzićN (2006) The bilia y a esia splenic mal o ma ion syn-
d ome: a 28-yea single-cen e e ospec i e s udy. J Pedia 149:
393–400. h ps://doi.o g/10.1016/j.jpeds.2006.05.030
9. Da enpo M, Pa sons C, Tizza d S, Hadzic N (2013) S e oids in
bilia y a esia: single su geon, single cen e, p ospec i e s udy. J
Hepa ol 59:1054–1058. h ps://doi.o g/10.1016/j.jhep.2013.06.012
10. de V ies W, Homan-Van de Veen J, Hulsche JB, Hoeks a-
Weebe s JE, Houwen RH, Ve kade HJ (2011) Twen y-yea ans-
plan - ee su i al a e among pa ien s wi h bilia y a esia. Clin
Gas oen e ol Hepa ol 9:1086–1091. h ps://doi.o g/10.1016/j.cgh.
2011.07.024
11. Decha un K, Leys CM, Wes KW, Finnell SM (2016) P ophylac ic
an ibio ics o p e en ion o cholangi is in pa ien s wi h bilia y a e-
sia s a us pos -Kasai po oen e os omy: a sys ema ic e iew. Clin
Pedia 55:66–72. h ps://doi.o g/10.1177/0009922815594760
12. De usso PA, Ye W, Shephe d R e al (2007) G ow h ailu e and
ou comes in in an s wi h bilia y a esia: a epo om he bilia y
a esia esea ch conso ium. Hepa ology 46:1632–1638. h ps://doi.
o g/10.1002/hep.21923
13. D ehe AM, A o a N, Fowle KB, No ak Z, B i WJ, Boppana SB,
Ross SA (2014) Spec um o disease and ou come in child en wi h
symp oma ic congeni al cy omegalo i us in ec ion. J Pedia 164:
855–859. h ps://doi.o g/10.1016/j.jpeds.2013.12.007
14. Escoba MA,JayCL,B ooksRM,Wes KW,Resco laFJ,
Molles on JP, G os eld JL (2006) E ec o co icos e oid he apy
on ou comes in bilia y a esia a e Kasai po oen e os omy. J
Pedia Su g 41:99–103. h ps://doi.o g/10.1016/j.jpedsu g.2005.
10.072
15. Fiscle B, S ensson JF, Neme h A (2009) Ea ly cy omegalo i us
in ec ion and long- e m ou come o bilia y a esia. Ac a Paedia 98:
1600–1602. h ps://doi.o g/10.1111/j.1651-2227.2009.01416.x
16. Flegal KM, Wei R, Ogden C (2002) Weigh - o -s a u e compa ed
wi h body mass index- o -age g ow h cha s o he Uni ed S a es
om he Cen e s o Disease Con ol and P e en ion. Am J Clin
Nu 75:761–766. h ps://doi.o g/10.1093/ajcn/75.4.761
17. G ee RM, Qui k P, Clegho n GJ, Shephe d RW (1998) G ow h
ho mone esis ance and soma omedins in child en wi h end-s age
li e disease awai ing ansplan a ion. J Pedia Gas oen e ol Nu
27:148–154. h ps://doi.o g/10.1097/00005176-199808000-00004
18. G ee R, Lehne M, Lewindon P, Clegho n GJ, Shephe d RW
(2003) Body composi ion and componen s o ene gy expendi u e
in child en wi h end-s age li e disease. J Pedia Gas oen e ol
Nu 36:358–363. h ps://doi.o g/10.1097/00005176-200303000-
00010
19. HadzićN, Da enpo M, Tizza d S, Singe J, Howa d ER, Mieli-
Ve gani G (2003) Long- e m su i al ollowing Kasai
po oen e os omy: is ch onic li e disease ine i able? J Pedia
Gas oen e ol Nu 37:430–433. h ps://doi.o g/10.1097/
00005176-200310000-00006
348 Eu J Pedia (2019) 178:341–349
20. Ha ley JL, Da enpo M, Kelly DA (2009) Bilia y a esia. Lance
374:1704–1713. h ps://doi.o g/10.1016/S0140-6736(09)60946-6
21. Hol RI, C ossey PA, Jones JS, Bake AJ, Po mann B, Miell JP
(1997) Hepa ic g ow h ho mone ecep o , insulin-like g ow h ac o
I, and insulin-like g ow h ac o -binding p o ein messenge RNA
exp ession in pedia ic li e disease. Hepa ology 26:1600–1606.
h ps://doi.o g/10.1002/hep.510260631
22. Hukkinen M, Ke ola A, Lohi J, Heikkilä P, Me as-Salmio L,
Jahnukainen T, Koi usalo A, Jalanko H, Paka inen MP (2018)
T ea men policy and li e his opa hology p edic bilia y a esia
ou comes: esul s a e na ional cen aliza ion and p o ocol biop-
sies. J Am Coll Su g 226:46–57. h ps://doi.o g/10.1016/j.
jamcollsu g.2017.09.009
23. Ka e FM, P ice MR, Bensa d DD, Sokol RJ, Na kewicz MR,
Smi h DJ, Lilly JR (1996) Long- e m esul s wi h he Kasai ope a-
ion o bilia y a esia. A ch Su g 131:493–496. h ps://doi.o g/10.
1001/a chsu g.1996.01430170039006
24. Kobayashi H, Yama aka A, Koga H, Okazaki T, Tamu a T, U ao M,
Yanai T, Lane GJ, Miyano T (2005) Op imum p ednisolone usage
in pa ien s wi h bilia y a esia pos po oen e os omy. J Pedia Su g
40:327–330. h ps://doi.o g/10.1016/j.jpedsu g.2004.10.017
25. Kuzne so a A, B ockho PB, Ch is ensen RHB (2017) Lme es
package: es s in linea mixed e ec s models. J S a So w 82:1–26.
h ps://doi.o g/10.18637/jss. 082.i13
26. Lampela H, Ri anen A, Kosola S, Koi usalo A, Rin ala R, Jalanko
H, Paka inen M (2012) Na ional cen aliza ion o bilia y a esia ca e
o an assigned mul idisciplina y eam p o ides high-quali y ou -
comes. Scand J Gas oen e ol 47:99–107. h ps://doi.o g/10.3109/
00365521.2011.627446
27. Lin YC, Chang MH, Liao SF, Wu JF, Ni YH, Tiao MM, Lai MW,
Lee HC, Lin CC, Wu TC, Lau BH, Tsai TC, Yang YJ, Chen AC,
Shih HH, Lee IH, Lee WC, Chen HL, Hsu HY, Chiou ST, he
Taiwan In an S ool Colo Ca d S udy G oup (2011) Dec easing
a e o bilia y a esia in Taiwan: a su ey 2004-2009. Pedia ics
128:530–536. h ps://doi.o g/10.1542/peds.2011-0742
28. Li esey E, Co ina Bo ja M, Sha i K, Alizai N, McClean P, Kelly
D, Hadzic N, Da enpo M (2009) Epidemiology o bilia y a esia
in England and Wales (1999-2006). A ch Dis Child Fe al Neona al
Ed 94:451–455. h ps://doi.o g/10.1136/adc.2009.159780
29. Lyka ie is P, Cha do C, Sokhn M, Gau hie F, Valaye J, Be na d
O (2005) Ou come in adul hood o bilia y a esia: a s udy o 63
pa ien s who su i ed o o e 20 yea s wi h hei na i e li e .
Hepa ology 41:366–371. h ps://doi.o g/10.1002/hep.20547
30. Ma inelli J, Habes D, Majed L, Gue ie C, Gonzalès E, Lingla A,
La ue C, Fu lan V, Pa ien e D, Bauja d C, B anche eau S, Gau hie
F, Jacquemin E, Be na d O (2018) Long- e m ou come o li e
ansplan a ion in child en: a s udy o 20-yea su i o s. Am J
T ansplan 18:1680–1689. h ps://doi.o g/10.1111/aj .14626
31. Mille WL, Flück CE (2014) Ad enal co ex and i s diso de s. In:
Spe ling M (ed) Pedia ic endoc inology, 4 h edn. Else ie Inc,
Philadelphia, pp 471–523.e1
32. Mu aji T, Higas ohimo o Y (1997) The imp o ed ou look o bili-
a y a esia wi h co icos e oid he apy. J Pedia Su g 32:1103–
1106. h ps://doi.o g/10.1016/S0022-3468(97)90408-5
33. Mussi-Pinha a MM, Yamamo o AY, Mou a B i o RM, de Lima
Isaac M, de Ca alho Oli ei a PF, Boppana S, B i WJ (2009)
Bi h p e alence and na u al his o y o congeni al cy omegalo i us
in ec ion in a highly se oimmune popula ion. Clin In ec Dis 15:
522–528. h ps://doi.o g/10.1086/600882
34. Ng VL, Habe BH, Magee JC, Mie hke A, Mu ay KF, Michail S,
Ka pen SJ, Ke ka N, Molles on JP, Rome o R, Rosen hal P,
Schwa z KB, Shneide BL, Tu melle YP, Alonso EM, She ke
AH, Sokol RJ, Childhood Li e Disease Resea ch and Educa ion
Ne wo k (CHiLDREN) (2014) Medical s a us o 219 child en wi h
bilia y a esia su i ing long- e m wi h hei na i e li e s: esul s
om a No h Ame ican mul icen e conso ium. J Pedia 165:539–
546. h ps://doi.o g/10.1016/j.jpeds.2014.05.038
35. Nigh ingale S, Ng VL (2009) Op imizing nu i ional managemen
in child en wi h ch onic li e disease. Pedia Clin N Am 56:1161–
1183. h ps://doi.o g/10.1016/j.pcl.2009.06.005
36. Ohi R, Ib ahim M (1992) Bilia y a esia. Semin Pedia Su g 1:115–
124
37. Pie o A, Kole zko B, Ca nielli V, Supe ina RA, Robe s EA, Fille
RM, Smi h J, Heim T (1989) Res ing ene gy expendi u e is in-
c eased in in an s and child en wi h ex ahepa ic bilia y a esia. J
Pedia Su g 24:534–538. h ps://doi.o g/10.1016/S0022-3468(89)
80500-7
38. R Co e Team (2017) R: a language and en i onmen o s a is ical
compu ing. R Founda ion o S a is ical Compu ing, Vienna.
A ailable a : h ps://www.R-p ojec .o g/
39. Saa i A, Sankilampi U, Hannila ML, Ki iniemi V, Kesseli K,
Dunkel L (2011) New Finnish g ow h e e ences o child en and
adolescen s aged 0 o 20 yea s: leng h/heigh - o -age, weigh - o -
leng h/heigh and body-mass-index o age. Ann Med 43:235–248.
h ps://doi.o g/10.3109/07853890.2010.515603
40. Saa i A, Sankilampi U, Hannila ML, Saha MT, Mäki ie O, Dunkel
L (2012) Sc eening o u ne synd ome wi h no el auxological
c i e ia acili a es ea ly diagnosis. J Clin Endoc inol Me ab 97:
E2125–E2132. h ps://doi.o g/10.1210/jc.2012-1739
41. Shinkai M, Ohhama Y, Take H, Ki agawa N, Kudo H, Mochizuki
K, Ha a a T (2009) Long- e m ou come o child en wi h bilia y
a esia who we e no ansplan ed a e Kasai ope a ion: > 20-yea
expe ience a a child en’s hospi al. J Pedia Gas oen e ol Nu 48:
443–450. h ps://doi.o g/10.1097/MPG.0b013e318189 2d5
42. Shneide BL, Abel B, Habe B, Ka pen SJ, Magee JC, Rome o R,
Schwa z K, Bass LM, Ke ka N, Mie hke AG, Rosen hal P,
Tu melle Y, Robuck PR, Sokol RJ, Childhood Li e Disease
Resea ch and Educa ion Ne wo k (2012) Po al hype ension in
child en and young adul s wi h bilia y a esia. J Pedia
Gas oen e ol Nu 55:567–573. h ps://doi.o g/10.1097/MPG.
0b013e31826eb0c
43. Sokol RJ, S all C (1990) An h opome ic e alua ion o child en
wi h ch onic li e disease. Am J Clin Nu 52:203–208. h ps://
doi.o g/10.1093/ajcn/52.2.203
44. So a R, Tolppanen EM, Pe heen upa J (1990) Va ia ion in g ow h
o leng h and weigh o child en. I. Yea s 1 and 2. Ac a Paedia
Scand 79:490–497. h ps://doi.o g/10.1111/j.1651-2227.1990.
b11502.x
45. Tijsseling D, Te Wolbeek M, De ks JB, de V ies WB, Heijnen CJ,
an Bel F, Mulde EJH (2018) Neona al co icos e oid he apy a -
ec s g ow h pa e ns in ea ly in ancy. PLoS One 13:e 0192162.
h ps://doi.o g/10.1371/jou nal.pone.0192162
46. Valaye J (1996) Con en ional ea men o bilia y a esia: long-
e m esul s. J Pedia Su g 31:1546–1551. h ps://doi.o g/10.
1016/S0022-3468(96)90174-8
47. Willo S, Uhlen S, Michaud L, B iand G, Bonne alle M, S ei R,
Go and F (2008) E ec o u sodeoxycholic acid on li e unc ion
in child en a e success ul su ge y o bilia y a esia. Pedia ics
122:1236–1241. h ps://doi.o g/10.1542/peds.2008-0986
48. Yeh TF, Lin YJ, Lin HC, Huang CC, Hsieh WS, Lin CH, Tsai CH
(2004) Ou comes a school age a e pos na al dexame hasone he -
apy o lung disease o p ema u i y. N Engl J Med 350:1304–1313.
h ps://doi.o g/10.1056/NEJMoa032089
49. Young S, Kwa a E, Azzam R, Sen ongo T (2013) Nu i ion assess-
men and suppo in child en wi h end-s age li e disease. Nu Clin
P ac 28:317–329. h ps://doi.o g/10.1177/0884533612474043
50. Zani A, Quaglia A, HadzićN, Zucke man M, Da enpo M (2015)
Cy omegalo i us-associa ed bilia y a esia: an ae iological and
p ognos ic subg oup. J Pedia Su g 50:1739–1745. h ps://doi.
o g/10.1016/j.jpedsu g.2015.03.001
Eu J Pedia (2019) 178:341–349 349