In ahepa ic Choles asis o P egnancy and Cance : A Coho S udy
Su i-Tuulia Hämäläinen1,2*, Kaisa Tu unen1, Ka i J Ma ila1, Elise Kosunen1,3 and Ma kku Sumanen1
1Depa men o Gene al P ac ice, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland
2Janakkala Heal h Cen e, Tu enki, Finland
3Cen e o Gene al P ac ice, Pi kanmaa Hospi al Dis ic , Tampe e, Finland
*Co esponding au ho : Su i-Tuulia Hämäläinen, Depa men o Gene al P ac ice, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland, Tel:
+358368011; E-mail: [email p o ec ed]
Recei ed da e: June 05, 2017; Accep ed da e: June 22, 2017; Published da e: July 3, 2017
Copy igh : © 2017 Hämäläinen ST, e al. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s
un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal au ho and sou ce a e c edi ed.
Abs ac
Objec i e: In a p e ious ques ionnai e s udy, mo e b eas cance s we e epo ed by women wi h in ahepa ic
choles asis o p egnancy (ICP) han by he con ols. The aim o his s udy was o es ablish whe he ICP is
associa ed wi h cance in he Finnish Cance Regis y da a, he s udy popula ion being he same coho as in he
ques ionnai e s udy.
Me hods: The s udy popula ion comp ised 571 women wi h ICP in a leas one p egnancy and 1,333 con ols
om Tampe e Uni e si y Hospi al in Finland du ing 1969–1988. The cance da a we e ob ained om he Finnish
Cance Regis y. The cance s we e classi ied by ICD-O-3 and diagnosed du ing he pe iod 1953−2013.
Resul s: In he ICP g oup, he odds a io o cance s (OR 1.26, 95% CI 0.96–1.64), and b eas cance in pa icula
(OR 1.36, 95% CI 0.91–2.03), was sligh ly highe han in he con ol g oup. Se en pe cen o he ICP g oup and
5.3% o he con ol g oup had b eas cance .
Conclusion: Based on his s udy he e is no a signi ican associa ion be ween ICP and cance . Ea lie
obse a ion in he ques ionnai e s udy ega ding associa ion be ween ICP and b eas cance canno be con i med
by his egis y based s udy.
Keywo ds In ahepa ic choles asis o p egnancy; ICP; Cance
In oduc ion
In ahepa ic choles asis o p egnancy (ICP) is a e e sible li e
diso de wi h p u i us as he main symp om, especially on he palms
and soles. An ele a ed se um bile acid and ansaminase concen a ion
is also equi ed o diagnosis [1]. In Eu ope, he incidence o ICP is
app oxima ely 1%, bu a es a y geog aphically [2]. In Finland, he
incidence is app oxima ely 1.0−1.5% [3] and in Sweden he incidence
is 0.5−0.75% [4]. Ho monal ac o s seem o con ibu e o he
pa hogenesis o ICP [5,6]. Es ogen may pa icipa e in he
de elopmen o choles asis [7] and p oges e one may impai hepa ic
bile homeos asis [8]. Gene ic ac o s a e known o be in ol ed in he
pa hogenesis; ICP is inhe i ed as a sex-limi ed dominan pheno ype
and mul iple genes a e in luen ial [9]. Mul id ug esis an p o ein 3
(MDR3) is associa ed wi h up o 15% o ICP cases [10,11].
En i onmen al ac o s may also ha e a ole in he pa hogenesis o he
diso de [12]. In addi ion, a posi i e amily his o y [13] and win
p egnancies aise he isk o ICP [14].
Excessi e exposu e o endogenous es ogen o e he li e ime may be
a causa i e ac o o b eas cance [15]. Ho monal, gene ic, and
en i onmen al ac o s a e known o ha e an impac on he ae iology
and pa hogenesis o cance s and ICP. Cance an igen 15-3 (CA15-3) is
a glycop o ein commonly ound in b eas cance cells, and i s le els in
se um e lec he amoun o b eas cance cells in he body. CA15-3
le els a e aised du ing p egnancy in gene al, bu hey a e highe in
ICP p egnancies han in con ols [16]. In an ex ensi e egis y-based
s udy, ICP was associa ed wi h an inc eased isk o la e hepa obilia y
cance . Hepa i is C in ec ion was s ongly associa ed wi h li e cance ,
bu a e adjus ing o his diagnosis, women wi h ICP we e s ill a
inc eased isk o li e malignancy. In addi ion, in a sepa a e analysis
excluding all women wi h galls one disease o cholangi is, women wi h
ICP had an inc eased isk o bilia y ee malignancies [17].
A low numbe o child bi hs has been associa ed wi h an inc eased
isk o b eas cance . Since mo he s wi h ICP ha e been ound o limi
hei child numbe mo e o en han con ols [18], i may be specula ed
whe he his has inc eased he incidence o b eas cance s. P ima y
heal hca e a anges almos exclusi ely ma e ni y ca e in he No dic
coun ies [19]. In Finland heal h cen es main ain ma e ni y heal h
clinics whe e a nu se o a midwi e and a Family Doc o a e esponsible
o ca e [20]. The ma e ni y heal h clinics in p ima y heal h ca e
usually de ec ICP. I a p egnan woman complains o p u i us he
ALAT and bile acids alues a e sc eened. Ei he o hese alues being
ele a ed he mo he is e e ed o an obs e ician [21]. I p u i us is
in ole able he mo he is e e ed o he obs e ic clinic wi hou wai ing
he esul s o he blood es .
A ques ionnai e s udy obse ed ha ICP may be associa ed wi h an
ele a ed isk o b eas cance [22]. Howe e , he s udy was based on
subjec i e in o ma ion ob ained om sel - epo s. The aim o he
p esen s udy was o in es iga e, using objec i e egis y da a, whe he
ICP has an associa ion wi h b eas cance o o he cance s when using
he same coho as he ques ionnai e s udy.
Family Medicine & Medical Science
Resea ch
Hämäläinen e al., Fam Med Med Sci Res 2017,
6:2
DOI: 10.4172/2327-4972.1000216
Resea ch A icle OMICS In e na ional
Fam Med Med Sci Res, an open access jou nal
ISSN:2327-4972
Volume 6 • Issue 2 • 1000216
Ma e ial and Me hods
All ICP p egnancies a Tampe e Uni e si y Hospi al (TUH) du ing
1969–1988 we e collec ed om he pa ien eco ds. F om 1969 o 1986,
ICD-8 was used a TUH. Because ICD-8 did no include a p ecise code
o ICP, we checked all he obs e ic codes ha migh con ain ICP:
637.9 Toxicosis NUD, 639.00 P u i us, 639.01 Ic e us g a is, 639.09
Nec osis acu a e subacu a hepa is, and 639.98 Aliae de ini ae.
The ea e , we checked he w i en diagnosis behind he code, and i i
e e ed o ICP, we included he case o u he selec ion. ICD-9 was
used be ween 1987 and 1988, and i con ained he app op ia e codes
6467A Hepa osis g a ida um and 6467X Hepa opa hia alia. The
diagnosis was e i ied om each pa ien eco d wi h he p esence o
he main symp om o i ching and abno mal labo a o y es esul s. A
leas one o he ollowing was equi ed: ASAT >35 U/l, ALAT >40 U/l,
o bile acids 6 μmol/l o mo e.
The s udy popula ion comp ised 687 ICP deli e ies. The da a
included some women wi h epea ed ICP deli e ies and each o hese
women was s udied as an indi idual case. The ICP g oup hus
con ained 575 women. The p oceeding and ollowing subjec s in he
ma e ni y wa d dia y we e aken as con ols o each ICP case. The e
we e 1,374 con ols in o al. The g oups we e compa able ega ding
age, educa ional le el, and body mass index. The deli e ies o mo he s
wi h ICP ook place a ea lie ges a ional weeks han hose o he
con ols. Fou women we e uled ou om he ICP cases and 41 om
he con ols because o a missing pe sonal iden i y code. The inal da a
comp ised 571 women wi h ICP and 1,333 con ols.
The cance da a we e ob ained om he Finnish Cance Regis y in
Janua y 2014 based on pe sonal iden i y codes. All physicians,
hospi als, and o he ele an ins i u ions ha e had an obliga ion o
epo e e y cance o he Finnish Cance Regis y since 1961. The
da abase con ains all he diagnosed cance s and cance dea hs in
Finland since 1961 and he mos o cance s since 1953, when
sys ema ic cance egis a ion was s a ed [23]. The Finnish Cance
Regis y also con ains in o ma ion on all dea h ce i ica es ha
men ion cance . The Regis y akes no ice o he comple eness and
accu acy o i s da a, and i s comple eness has been shown o be o e
99% [24]. The Regis y is upheld by he Na ional Ins i u e o Heal h
and Wel a e o Finland. The s udy da a included all epo ed cance s o
he coho du ing 1953–1960, all egis e ed cance s du ing 1961–2013,
and he loca ion and beha iou o he cance . The cance s we e
epo ed by ICD-O-3 opog aphical codes [25]. Women who had had
mo e han one cance we e also included in he s udy. The cance s
we e classi ied by ICD-O-3 codes in o la ge subg oups. Cance
beha iou was classi ied as benign, unclea beha iou , ca cinoma in
si u, o malignan .
The da a we e analysed using he SPSS Sys em o Windows, Ve sion
22.0. The esul s a e p esen ed as equencies and pe cen ages.
S a is ical signi icance was es ed wi h a chi-squa ed es . Bina y
logis ic eg ession analysis was pe o med o ob ain odds a ios (OR)
and 95% con idence in e als (CI). The dependen a iable was “ICP
o no ”. T- es was pe o med o explo e di e ence ega ding age a he
diagnose momen o cance . The coho did no ob ain in o med
consen because he s udy is e ospec i e and does no ha e an e ec
on ea men . The s udy has he app o al o he Regional E hics
Commi ee o Tampe e Uni e si y Hospi al (R02149) and he Na ional
Ins i u e o Heal h and Wel a e in Finland (THL/1051/5.05.00/2014).
Resul s
In he ICP g oup, 96 women (16.8%) had been diagnosed wi h a
leas one cance , compa ed o 185 women (13.9%) in he con ol g oup.
The di e ence was no s a is ically signi ican (p=0.098). Mo he s wi h
ICP had a sligh ly highe isk o cance (OR 1.26, 95% CI 0.96–1.64)
han he con ol mo he s. None o he mo he s wi h ICP and i een
(1.1%) o he con ols had been diagnosed wi h wo o mo e sepa a e
cance s (p=0.011). One o he con ols had had h ee sepa a e cance s.
Th ee women had been diagnosed wi h a cance be o e labou and all
o hem we e con ols.
The occu ence o cance s is p esen ed in Table 1. B eas cance was
he mos common cance in bo h g oups. The mo he s wi h ICP had a
sligh ly highe isk o b eas cance (OR 1.36, 95% CI 0.91–2.03) han
he con ol mo he s. B eas cance was diagnosed a a sligh ly olde age
in he ICP g oup han in he con ol g oup bu he di e ence was no
s a is ically signi ican .
ICD-10
code
Cance Mo he s
wi h ICP
n=571
Con ol
mo he s
n=1,333
Di e ence
n % n % %
uni s
p-
alue
C50 B eas 40 7.0 70 5.3 1.7 0.133
C73-
C75
Thy oid and o he
endoc ine glands
6 1.1 5 0.4 0.7 0.075
C64-
C68
U ina y ac 4 0.7 3 0.2 0.5 0.116
C42 Haema opoie ic and
e iculoendo helial
sys ems
2 0.4 2 0.2 0.2 0.382
C30-
C39
Respi a o y and
in a ho acic o gans
1 0.2 3 0.2 0.0 0.827
C40-
C41
Bone and a icula
ca ilage
1 0.2 3 0.2 0.0 0.827
C80 Unknown p ima y si e 1 0.1 1 0.1 0.0 –
C00-
C14
Lip, o al ca i y, and
pha ynx
0 0.0 1 0.1 -0.1 0.513
C15-
C26
Diges i e o gans 7 1.2 19 1.4 -0.1 0.731
C45-
C49
Meso helial and so
issue
0 0.0 1 0.1 -0.1 0.513
C43-
C44
Melanoma and o he
malignan neoplasms o
skin
18 3.2 38 2.9 -0.1 0.721
C51-
C58
Female geni al o gans 14 2.5 35 2.6 -0.1 0.826
C69-
C72
Eye, b ain, and o he
pa s o cen al ne ous
sys em
3 0.5 8 0.6 -0.1 0.844
C77 Lymph nodes 2 0.4 7 0.5 -0.1 0.610
Table 1: The occu ence o cance s in mo he s wi h ICP and he
con ols.
Ci a ion: Hämäläinen ST, Tu unen K, Ma ila KJ, Kosunen E, Sumanen M (2017) In ahepa ic Choles asis o P egnancy and Cance : A Coho
S udy. Fam Med Med Sci Res 6: 216. doi:10.4172/2327-4972.1000216
Page 2 o 4
Fam Med Med Sci Res, an open access jou nal
ISSN:2327-4972
Volume 6 • Issue 2 • 1000216
Melanoma and o he malignan neoplasms o he skin as well as
cance s o he emale geni al o gans we e among he mos common
cance s in bo h g oups. Cance s o he hy oid and o he endoc ine
glands and u ina y ac cance we e mo e common in he mo he s
wi h ICP han in he con ols, bu he di e ences we e no s a is ically
signi ican . O he diges i e o gan cance s, hepa obilia y cance was
also examined sepa a ely. Hepa obilia y cance was ound in one
mo he wi h ICP and among none o con ols. Mos o he cance s
(nea ly 90%) we e malignan in bo h g oups (Table 2). The di e ence
be ween he g oups was no s a is ically signi ican (p=0.758).
Cance beha iou Mo he s wi h ICP (n=96) (%) Con ol mo he s (n=185) (%)
Malignan 87.5 86.5
Ca cinoma in si u 6.3 5.4
Unclea beha iou 0.0 1.1
Benign 6.3 7.0
Table 2: Cance beha iou acco ding o ICD-O-3 among mo he s wi h ICP and he con ols.
The mo he s wi h ICP had been diagnosed wi h cance a a sligh ly
olde age, he mean age being 53.0 yea s in he ICP g oup and 51.8
yea s in he con ol g oup. The di e ence was 1.2 yea s (p=0.315). The
mean age o mo he s who had no been diagnosed wi h cance was
61.5 yea s among ICP mo he s and 61.3 yea s among con ols in
31/12/2013.
Discussion
The ICP g oup and he con ol g oup e inced mino di e ences in
mos o he s udy ou come measu es. The indings a e in ag eemen
wi h o me obse a ions on he associa ion o cance and ICP. In he
con ol g oup, he e we e women who had been diagnosed wi h wo o
mo e sepa a e cance s, bu in he ICP g oup each woman wi h cance
had been diagnosed wi h only one cance . ICP was associa ed wi h a
sligh ly highe isk o cance , especially b eas cance .
The aim o he p esen s udy was o es ablish whe he ICP is
associa ed wi h an inc eased isk o cance s, and especially o b eas
cance , which was he esul ound om he ea lie s udy based on sel -
epo s. Despi e he small loss o cases, he da a we e adequa e. The
da a ob ained om he Finnish Cance Regis y can be conside ed
eliable.
Medica ions may ha e an impac on he isk o cance . O e he
pas decades, a ious ea men s ha e been used o ICP. We ha e no
collec ed in o ma ion abou he medica ion o ICP among ou s udy
popula ion, and consequen ly he ole o medica ion ega ding he isk
o cance canno be e alua ed.
A ecen Swedish s udy did no ind any clea associa ion be ween
o e all cance and ICP [17], which is in ag eemen wi h ou indings.
In he same s udy, an inc eased isk o la e hepa obilia y cance in
women wi h ICP was ound (li e cance : HR 3.61; and bilia y ee
cance : HR 2.62). In he a o emen ioned s udy, he occu ence o
hepa obilia y cance s was small in he ICP g oup (0.1–0.2%). Based on
he abo e s udy, he expec a ion alue o ind any hepa obilia y cance s
in ou s udy was e y small. Howe e , one hepa obilia y cance was
ound in ou ICP g oup, which exceeds he expec a ion alue.
The e is highe isk o hepa obilia y disease and pa icula ly ch onic
hepa i is among women wi h a his o y o ICP [26,27]. The la e
disease causes li e ci hosis and is o en complica ed by hepa ocellula
cance [17]. Also choleli hiasis and ch onic cholangi is a e associa ed
wi h ICP [26,27] and a e associa ed wi h gallbladde and
cholangiocellula cance [17].
The Swedish egis y s udy did no ind any associa ion be ween
b eas cance and ICP (HR 1.03). In ou s udy, mo he s wi h ICP had a
sligh ly highe isk o b eas cance han he con ol mo he s (OR
1.36), al hough he di e ence was no s a is ically signi ican . The
occu ence o b eas cance was lowe in he Swedish popula ion
(1.6%) han in ou Finnish popula ion. Women’s isk o ha ing b eas
cance be o e he age o 75 is 9.9% in Finland and 9.6% in Sweden [28].
Ou longe ollow-up ime and he younge age o mo he s in he
Swedish s udy migh explain he di e ence. Ne e heless, he coho
should be ollowed e en longe because now he coho ep esen s
hose who had been diagnosed wi h cance a a ai ly young age.
P ema u e deli e y (ges a ion weeks <37) seems o inc ease he
mo he ’s isk o b eas cance la e in li e [29]. Fo me ly, i has been
ound ha ICP is associa ed wi h an ele a ed isk o deli e y in
ges a ion weeks unde 37 [14]. I can be conside ed ha p ema u e
deli e y may inc ease he numbe o b eas cance cases among ICP
women.
A ques ionnai e s udy obse ed ha he women wi h ICP epo ed
mo e b eas cance (6.3% s. 3.7%, p=0.047) [22]. In ou s udy, b eas
cance was ound among 7.0% in he ICP g oup and among 5.3% in
he con ol g oup, he coho being he same as in he ques ionnai e
s udy. In his egis y s udy, howe e , he di e ence be ween he
g oups is no s a is ically signi ican .
ICP has ound o ha e a mul i ac o ial gene ic base. I may be
specula ed ha ICP is one exp ession o a la ge g oup o gene ic
diseases. Ho monal ac o s may be ele an in he pa hogenesis o ICP
and b eas cance [5,6,15]. I may be specula ed whe he he same
ho monal ac o s ha e an e ec on bo h diseases.
This is he i s Finnish egis y s udy on he po en ial associa ion
be ween ICP and cance . Acco ding o he w i e s’ knowledge he e is
only one egis y based s udy in es iga ing he associa ion be ween
ICP and cance [17], and he e o e he indings in his s udy may be
conside ed unique. Howe e , o me obse a ions ega ding he
associa ion be ween ICP and b eas cance in he ques ionnai e s udy
could no be con i med by his egis y based s udy. A la ge numbe
o ICP women and a longe ollow-up ime o he coho migh be
needed o con i m he esul s. Based on his s udy doc o s do no ha e
o change hei ea ing s a egies and sc een cance s because a woman
has a his o y o ICP.
Ci a ion: Hämäläinen ST, Tu unen K, Ma ila KJ, Kosunen E, Sumanen M (2017) In ahepa ic Choles asis o P egnancy and Cance : A Coho
S udy. Fam Med Med Sci Res 6: 216. doi:10.4172/2327-4972.1000216
Page 3 o 4
Fam Med Med Sci Res, an open access jou nal
ISSN:2327-4972
Volume 6 • Issue 2 • 1000216
Acknowledgmen s
The Cen e o Gene al P ac ice o he Pi kanmaa Hospi al Dis ic
unded he s udy by se ling he dues om he Na ional Ins i u e o
Heal h and Wel a e in Finland and he Finnish Cance egis y. We a e
g a e ul o he Na ional Ins i u e o Heal h and Wel a e in Finland and
he Finnish Cance Regis y o hei consen o use he egis y da a.
Con lic o In e es
The au ho s ha e no con lic s o in e es .
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S udy. Fam Med Med Sci Res 6: 216. doi:10.4172/2327-4972.1000216
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Fam Med Med Sci Res, an open access jou nal
ISSN:2327-4972
Volume 6 • Issue 2 • 1000216