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Clinics and Research in Hepatology and Gastroenterology (2016) xxx, xxx—xxx

Available online at

ScienceDirect
www.sciencedirect.com

MINI REVIEW

The pathophysiology of intrahepatic

cholestasis of pregnancy
Peter H. Dixon , Catherine Williamson ∗

Division of Women’s Health, 2.30W Hodgkin Building, King’s College London, Guy’s Campus,
SE1 1UL London, United Kingdom

Summary A number of liver disorders are specific to pregnancy. Amongst these, intrahepatic
cholestasis of pregnancy (ICP), also known as obstetric cholestasis (OC), is the commonest,
affecting approximately 1 in 140 UK pregnancies. Patients commonly present in the third
trimester with severe pruritus and deranged serum liver tests; bile acids are elevated, in severe
cases >40 ␮mol/L. Although the disease is considered relatively benign for the mother, increased
rates of adverse fetal outcomes, including stillbirth, are associated with ICP. As our knowledge
of the mechanisms underlying bile acid homeostasis has advanced in the last 15 years our under-
standing of ICP has grown, in particular with respect to genetic influences on susceptibility to
the disease, the role of reproductive hormones and their metabolites and the possible identity
of the pruritic agents. In this review, we will describe recent advances in the understand-
ing of this condition with a particular emphasis on how aspects of genetic and reproductive
hormone involvement in pathophysiology have been elucidated. We also review recent devel-
opments regarding our knowledge of placental and fetal pathophysiology and the long-term
health consequences for the mother and child.
© 2016 Elsevier Masson SAS. All rights reserved.

Introduction native Indian descent [1]. Recently however rates have been
reported as much lower, between 1.5—4% [2]. In Europe, ICP
Intrahepatic cholestasis of pregnancy (ICP) is a liver dis- has been reported to occur more commonly in winter months
ease specific to pregnancy, affecting approximately 1 in in some countries. Further details of the epidemiology of ICP
140 UK pregnancies with a varied global incidence, both are reviewed in [3].
geographically and with ethnicity. Historically the most com- Affected women usually present in the third trimester of
mon rates were reported in Chile, particularly in women of pregnancy with pruritus, commonly localised to the palms
of the hands and the soles of the feet. Some women may
present much earlier however, occasionally as soon as eight
∗ Corresponding author.
weeks gestation. There is no rash associated with ICP, but
E-mail address: catherine.williamson@kcl.ac.uk affected women can have dermatitis artefacta secondary
(C. Williamson). to scratching. Jaundice is rarely present. Biochemical

http://dx.doi.org/10.1016/j.clinre.2015.12.008
2210-7401/© 2016 Elsevier Masson SAS. All rights reserved.

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2 P.H. Dixon, C. Williamson

abnormalities associated with the condition are deranged cell membranes. The process of bile formation is an energy-
serum liver tests and raised serum bile acids although the driven process, characterised by export of molecules from
extent of these abnormalities is extremely variable. Serum hepatocytes into the biliary tree against a steep concentra-
bilirubin is raised in a small proportion of cases. Serum bile tion gradient. Bile acids are effluxed into the bile canaliculi
acids are increasingly recognised as the most definitive lab- by a specific ATP-dependent transporter, the bile salt export
oratory test for diagnosis [4—7]. pump (BSEP, systematic name ABCB11). In addition to the
Increasingly ICP is recognised to be associated with an bile acids themselves, a number of biliary transport pro-
abnormal metabolic profile. In addition to the hepatic fea- teins are responsible for export of other molecules into
tures there is an increased prevalence of dyslipidaemia bile (Fig. 1). The second major component of bile, phos-
and impaired glucose tolerance [8,9], and maternal co- phatidyl choline (PC), is flopped into the biliary tree by the
morbidity, e.g. gestational diabetes and pre-eclampsia, ATP-coupled transporter MDR3, also known as ABCB4. PC
occurs more commonly in women with ICP [10,11]. The has a vital protective role in the intraluminal space. Dur-
disease usually resolves soon after delivery, and if the bio- ing bile formation bile acids exported by BSEP form mixed
chemical and clinical abnormalities do not return to normal micelles with PC. These complexes serve to protect the
by 4—6 weeks postpartum, investigations should be per- luminal epithelium from the toxic and detergent effects of
formed to exclude alternative underlying liver pathology. bile salts and hence allow their secretion without damage
The severity of pruritus can be extremely distressing. to the surrounding cells. PC secretion, concurrent with bile
ICP is associated with increased rates of adverse preg- salts, is hence essential to maintain adequate bile flow [23].
nancy outcome, including spontaneous preterm labour, fetal Aside from these two major components, bile also
distress, fetal asphyxial events and intrauterine death contains other organic ion conjugates, exported from
[12,13]. A number of studies have demonstrated an asso- the hepatocytes via another ATP-driven transporter, MRP2
ciation between higher maternal serum bile acid levels and (ABCC2). These include bilirubin, drug conjugates and other
increased rates of fetal complications, in particular when organic ions. A heterodimeric protein complex of two mem-
serum bile acids are raised above 40 ␮m/L [14,15]. In ICP brane proteins, ABCG5 and ABCG8, also exports cholesterol.
maternal bile acids cross the placenta and accumulate, MDR1 (ABCB1), a close homologue of ABCB4 but with much
resulting in a reversal of the trans-placental gradient of bile broader substrate specificity, exports other drug conjugates.
acid concentrations [16]. Phosphatidyl serine is flipped from the outer to the inner
Ursodeoxycholic acid (UDCA) is the most commonly used membrane by another transporter, ATB8B1 (also known as
treatment for ICP. This drug is a naturally-occurring tertiary FIC1) (Fig. 1).
bile acid, normally comprising about 3% of the human bile Bile is stored in the gall bladder until release, driven
acid pool. Small studies show evidence of maternal benefit by the action of post-prandial cholecystokinin. In the small
(confirmed by a recent meta-analysis [17]) but no study has intestine, bile acids emulsify dietary fats, lipids and fat-
been powered to confirm a feto-protective effect of UDCA soluble vitamins. Bacteria in the gut are responsible for a
treatment. However the same meta-analysis was strongly range of modifications, including de-conjugation and dehy-
suggestive of a benefit to fetal outcomes, although the num- droxylation, resulting in the formation of secondary bile
ber of cases in whom there was a comparison of UDCA and acids, namely deoxycholic acid and lithocholic acid.
placebo was relatively small. In some cases rifampicin is Re-absorption via enterocytes is accomplished by spe-
used as a second-line treatment [18]. For a more compre- cific transporter systems (Fig. 1), and subsequently bile
hensive review of ICP treatment see [5,19]. salts return to the liver via the hepatic portal vein. On the
Although ICP resolves shortly after delivery, accumulat- hepatocyte sinusoidal membrane, the sodium-dependent
ing evidence points to lifelong consequences for the mother taurocholate co-transporter peptide (NTCP) is responsible
and child. Population-based analysis of a large cohort of for the majority of uptake, with the remainder (>20%) medi-
ICP cases identified a substantial increase in risk for hepa- ated by organic anion co-transporting polypeptides (OATPs,
tobiliary disease later in life [20] in addition to enhanced also known as SLCOs). This process of active recycling and
susceptibility to hepatobiliary cancer, immune disease and circulation is extremely efficient. The liver takes up approxi-
cardiovascular disease [21]. mately 95% of bile acids with the remaining 5% lost in faeces.
Beyond the adverse fetal outcomes, an impact of ICP This loss is replaced by de novo synthesis as described above.
on the metabolic health of adolescent offspring has been In addition to the dietary emulsification role described
shown, indicating a programming effect of the in utero expo- above, bile acids are increasingly recognised as key
sure to high bile acids [22]. metabolic signalling molecules, acting via a number of
receptor-controlled pathways that impact cholesterol, lipid
and carbohydrate homeostasis as well as the immune sys-
Bile formation and enterohepatic circulation tem.
Bile acids are extremely cytotoxic at low concentrations
Bile acids are synthesized in the liver and are the primary and hence their synthesis and transport is highly regulated
endpoint of cholesterol catabolism. A multi-step enzymatic by homeostatic mechanisms. In hepatocytes (and entero-
pathway, involving at least 17 enzymes, accomplishes this. cytes) the nuclear receptor FXR (farnesoid X receptor)
Synthesis is in part governed by the initial rate-limiting step, functions as the principal sensor of intracellular bile acid
the 7-alpha hydroxylation of cholesterol, by the cytochrome levels. Primary bile acids bind FXR and following hetero-
P450 enzyme CYP7A1. Subsequent to synthesis, the primary dimerization with RXR (retinoid-X receptor) the receptor
bile acids, cholic acid and chenodeoxycholic acid are con- complex translocates to the nucleus and binds to response
jugated with glycine or taurine, making them impervious to elements in the promoters of target genes. These target

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ICP pathophysiology 3

Figure 1 The molecular basis of the enterohepatic circulation of bile acids, showing some of the candidate loci for ICP suscepti-
bility reviewed in this article. Sinusoidal bile acid uptake (>80%) is facilitated by the sodium-dependent taurocholate uptake pump
(NTCP, SLC10A1) together with SLCO1B1 (<20%). In addition to BSEP (ABCB11), phosphatidyl choline is secreted via MDR3 (ABCB4).
Other transporters involved in biliary formation and secretion are shown including the multidrug resistance protein 1 (MDR1, ABCB1),
breast cancer resistance protein (BCRP, ABCG2), the sterol transporter complex ABCG5/8 and the multidrug resistance related pro-
tein 2 (MRP2, ABCC2), which exports bilirubin. Also shown is ATP8B1, a type 4 P-type ATPase, which is also crucial for bile formation
and canalicular membrane integrity. The nuclear receptor FXR (NR1H4) is also shown. Reabsorption of bile acids across the ileal
enterocyte brush border membrane is via the apical sodium-dependant bile acid transporter ASBT (SLC10A2). Following activation
of ileocyte FXR and FGF19 expression, export from the ileocyte back into the portal circulation is via the heteromeric transporter
OSTa/b. BA: bile acid; Chol: cholesterol; PC: phosphatidyl choline; PS: phosphatidyl serine; BR: bilirubin; GSH: reduced glutathione.
For details of genetic studies of these loci see Table 1.

genes include genes responsible for uptake, synthesis and No distinct male phenotype has been identified, although
export; hence FXR co-ordinately regulates hepatocellular related individuals often have gallstones. Several other lines
bile acid levels [24,25]. of evidence indicate a significant genetic component to the
Bile acid signalling at the cellular surface in some tis- pathophysiology, including elevated sibling risk in affected
sues occurs though the membrane-bound G-protein coupled women, and significant variability of disease frequency in
receptor TGR5, resulting in activation of different signalling different populations (likely due to different genetic back-
pathways. ground) [28].
Homozygous mutations of some of the hepatobiliary
transporters described above were identified as underlying
Maternal pathophysiology: genetic a number of severe paediatric liver diseases, collec-
susceptibility tively known as progressive familial intrahepatic cholestasis
syndromes (PFICs) [29]. Homozygous or compound het-
Several large pedigrees have been reported where ICP is erozygous mutations of: ATP8B1 (a phosphatidyl serine
inherited as a sex-limited dominant phenotype [26,27]. flippase), ABCB11 (the bile salt export pump) and ABCB4 (a

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4 P.H. Dixon, C. Williamson

phosphatidyl choline floppase) cause PFIC1-3 respectively. of ICP. Several studies have identified both novel and
A milder form of these diseases, benign recurrent intrahep- recurrent mutations in ICP cohorts [41—43]. The relatively
atic cholestasis (BRIC) has also been described, and there common Caucasian PFIC2 mutations (E297G and D482G) have
appears to be variable severity of cholestasis in associa- also been identified. Based on studies published to date,
tion with different homozygous and heterozygous mutations 5% or more ICP cases may harbour a mutation in this gene
When mutations of these genes were identified, ICP occurred (Table 1). As with ABCB4, functional studies, mini-gene
more frequently than expected. This led to investigations of construct analysis and immunohistochemistry have been
the role of these genes in ICP. performed to delineate genotype/phenotype correlations
[44—46].
The common valine 444 alanine (V444A) polymorphism
ABCB4
(rs2287622) has been investigated in ICP [41] along with a
number of other liver diseases. Clear evidence exists for
There have been numerous studies of the canalicular trans-
an association with ICP although the most recent analy-
porter ABCB4 in ICP. Initial studies were driven by the
sis identified a stronger association from a nearby marker
identification of homozygous mutations of this gene in PFIC
(rs7577650), suggesting that this SNP may be in linkage dis-
[30]. This initial discovery included the observation that
equilibrium with the underlying variant; further studies are
mothers of these children, obligate heterozygous carriers
needed to confirm or refute this. A second, independent
of ABCB4 mutations, had a higher frequency of ICP. This led
association was uncovered at this locus with another SNP
to the identification of an ICP pedigree in the absence of
(rs3815676) but at a much lower frequency [35]. As with the
PFIC with a segregating mutation [31], and subsequently the
ABCB4 variant rs2109505 these changes are not mutations
identification of the first sporadic case of ICP caused by a
and may only have a small effect on mRNA transcription or
heterozygous mutation [32].
protein function and hence a small effect on disease risk.
A considerable number of studies have expanded the
range of mutant alleles in this gene associated with ICP
(Table 1). Of note, heterozygous mutations of ABCB4 are Other loci
implicated in a spectrum of cholestatic liver disease, includ-
ing inherited diseases such as low-phospholipid associated
A number of other canalicular transporters are involved in
cholelithiasis (LPAC) syndrome [33], and acquired cholesta-
bile formation and membrane stability in hepatocytes as
sis such as drug-induced liver injury. Mutations have also
described above. Studies suggest a possible role for ATP8B1
been reported in young women who have not been pregnant
mutations in limited cases [47,48], and a possible role for
following onset of cholestasis induced by the use of hor-
ABCC2 in a South American cohort [49], although the ABCC2
monal contraception [34].
findings were not replicated in a larger European cohort.[35]
In addition to rare variants, a common variant in close
As described above, FXR is the key homeostatic sensor of
proximity to the splice site but not altering the protein
bile acid levels in hepatocytes. Genetic variation at and
sequence, rs2109505, has been found to be associated with
around this gene has been examined in ICP cohorts and a
ICP [35]. In a recent whole-genome sequencing analysis,
number of variants identified with functional effects [50].
the same variant was found to be associated with gallstone
However, the rare frequency of these alleles implies only a
disease [36]. In the same study, imputed genotypes of 266
small contribution to overall population susceptibility to ICP.
cases of ICP and 422 relatives identified several rare vari-
In addition to these, many other loci have been exam-
ants of ABCB4 specific to this population and some of the
ined, usually in small studies with low power to detect
common single nucleotide polymorphisms (SNPs) believed to
anything other than near Mendelian like effects (Table 2).
be associated with ICP in studies in other European popula-
No robust evidence exists to date for the involvement of
tions. These common population variants are not mutations;
any other loci. However a recent novel population-genetics
they are believed to have a minor effect on protein function
approach (admixture mapping) may be successful in identi-
hence alter risk to a small degree.
fying new genomic regions of interest [51].
In vivo studies of mutant proteins have proved challeng-
ing for this gene but recently several groups have reported
successful expression of the protein in different cell line Maternal pathophysiology: pruritus
systems and characterisation of the effect of specific point
mutations, the most recent study being a comprehensive
The pruritus associated with ICP can be severely distressing
classification of the effect of a series of such mutations
and result in excoriations in an attempt to relieve the symp-
[37—40]. These approaches are of particular relevance to
toms. Previously the bile acids themselves were considered
ICP and to all of the ABCB4-related pathologies as pheno-
to be a possible pruritic agent, but the levels seen in ICP
type/genotype relationships are central to an understanding
do not correlate well with self-reported itch scores. How-
of how mutations cause such a spectrum of phenotypes. In
ever the identification of a TGR5-mediated bile-acid induced
addition, disease associated mutations may have an effect
signalling pathway has been demonstrated in sensory nerves
on treatment response.
[52]. Progesterone sulphates were recently shown to cor-
relate with the severity of pruritus in ICP, in addition to
ABCB11 affecting TGR5-dependent scratch responses [53].
Another candidate pruritogen is lysophosphatidic acid, a
Heterozygous mutations of this transporter have been recog- serum lipid involved in a number of signalling pathways and
nised as having a smaller but important role in the aetiology produced by the action of the enzyme autotaxin. Identified

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Table 1 Genetic studies of ICP; genes that influence biliary transport.

Gene name Protein Cohort studied Ethnicity Results and notes Reference

ABCB4 Multidrug resistance 3 Single large pedigree French Co-existence of PFIC3 [31]
protein (MDR3), flops and ICP, identification of
phosphatidyl choline 1712delT in
into lumen heterozygous mothers
8 cases sequenced for Caucasian Single mutation [32]
entire gene identified, A546D
57 cases screened for Finnish Mutation reported in [90]
1712delT mutation single French family not
seen in Finnish cohort
14 cases (entire gene Caucasian R150K variant identified [91]
sequenced) plus in one family and extra
screening for known unrelated case. SNP also
variation in 170 found to be associated
further cases with ICP
Single case of Caucasian Heterozygous mutation [92]
cholelithiasis, identified, D535G,
cholestasis of transmitted to daughter
pregnancy and biliary who had ICP
cirrhosis
20 cases screened for Caucasian Single mutations [93]
5 selected exons of identified, R144X
ABCB4
80 cases plus 80 Italian Three heterozygote [94]
controls screened for variants identified
mutations of exon 14 (E528D, R549H, G536R)
Single large pedigree Mennonite 54bp in-frame deletion [95]
caused by cryptic splice
site activation identified
Above study extended Italian Three further variants [96]
to 96 women and identified (R590Q, R652G
three exons screened and T667I)
10 cases with raised Italian Novel splicing mutation [97]
GGT and recurrent missense
mutation(R590Q)
identified
Cohort of 50 ICP Caucasian Eight mutations [98]
cases sequenced identified (R144X, S320F,
T775M and five cases of
R590Q)
59 patents (mix of ICP French 16 point mutations/small [99]
and CIC) sequenced, indels identified and a
large indels also single whole-gene
analysed heterozygous deletion in
CIC case
Sequencing of a large French Six truncation mutations [100]
LPAC cohort including and 17 missense
ICP cases mutations identified in
ICP part of cohort
Single case of severe Hispanic Heterozygous mutation [101]
recurrent early onset identified (W164G)
ICP
Single case of NK Heterozygous mutation [102]
recurrent gallstones identified (P726L)
and ICP
Large cohort of adult Italian Two heterozygous [103]
patients including 4 mutations identified
with ICP sequenced (L859W and S320F)

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Table 1 (Continued)

Gene name Protein Cohort studied Ethnicity Results and notes Reference

ABCB11 Bile salt export pump 57 cases and 115 Finnish Single locus SNP plus [104]
(BSEP), exports controls typed for haplotype analysis
monovalent bile salts two SNPs showed evidence of
into lumen association
142 cases and two Finnish Failed to reproduce [105]
control groups of 100 above association
each
491 cases screened Caucasian E297G mutation [42]
for five known mutant identified in four cases,
alleles and typed for D482 once and N591S
V444A polymorphism twice. The 444A SNP was
found to be associated
with ICP
ABCC2 Multidrug resistance 70 cases and 112 South Association between [49]
related protein 2 controls analysed American rs3740066 in exon 28 and
(MRP2); exports four 6 SNPs ICP
organic anions
including bilirubin
into bile
ATP8B1 Familial intrahepatic Sixteen cases Caucasian D70N found in three [48]
cholestasis 1 gene sequenced, variants cases. R867C found in a
(FIC1), flips detected then single case. F305I seen in
phosphatidyl serine analysed in 182 a single case and single
into hepatocyte from patients and 120 control
lumen controls
Linkage suggested Finnish 17 sequence changes [47]
involvement of loci in detected, two novel
four families. 176 missense mutations
cases screened (N45T, K203R) suggested
to predispose to ICP
NR1H4 Farnesoid-X receptor 92 cases sequenced, Caucasian Four novel heterozygous [50]
(FXR), master subsequent and variants identified
regulator of bile acid case-control study of mixed (-1g>t, M1V, W80R,
homeostasis 293 cases and 290 M173T). M173T
controls plus 49 cases associated with ICP in
and 59 controls combined analysis,
functional defects shown
for 3 variants
6 cases sequenced NK Single heterozygous [106]
together with 2 variant identified (-1g>t)
drug-induced
cholestasis cases
NR1I2 Pregnane-X receptor Sequencing of entire Caucasian Polymorphisms identified [107]
(PXR), sensor of gene in 121 cases, at identical frequencies
xenobiotics exon 2 in a further in cases and controls
226 cases
4 tag SNPs plus three South Association reported [108]
other functional America between rs2461823 and
variants typed in 101 ICP
cases and 171

Multiple loci analysed

ABCB4, ABCB11, 16 individuals from Finnish Linkage analysis (plus [109]

AT8B1 two Finnish ICP ABCB4 sequencing) to
families exclude 3 loci

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ICP pathophysiology 7

Table 1 (Continued)

Multiple loci analysed

ABCB4, ABCB11 21 cases and 40 Caucasian Single ABCB11 variant [41]

controls sequenced (N591S) and two ABCB4
for coding region of variants (S320F and
two genes G762E) plus four ABCB4
splicing mutations
identified
ABCB4, ABCB11 Single severe case Moroccan Combination of [110]
sequenced for both homozygous ABCB4
genes mutation (S320F) and
V444A ABCB11
polymorphism identified
ABCB4, ABCB11 Haplotype study of 52 Caucasian Single haplotype of [111]
cases and 52 controls ABCB4 seen more
commonly in cases and
two seen more
commonly in controls.
ABCB11 haplotypes
showed no differences in
distribution
ABCB11, ABCC2 Coding SNP of ABCB11 Caucasian V444A polymorphism of [112]
and two coding SNPs ABCB11 associated with
of ABCC2 analysed in ICP
42 and 33 cases
respectively
ABCB4, ABCB11 Single case of NK Heterozygous stop codon [113]a
recurrent ICP and in ABCB4 and V444A
choledocholithiasis polymorphism identified
ABCB4, ABCB11, Sequencing of single French V444A polymorphism of [114]
ATP8B1 severe case ABCB11 found in
homozygous state
ABCB4, ABCB11, Sequencing of single NK Heterozygous mutation [115]
NR1H4 case for ABCB4 and in ABCB4 (S320F)
ABCB11 and typing together with V444A in
for 5 NR1H4 SNPs ABCB11 and -1g>t in
NR1H4
ABCB4, ABCB11, Single case with NK R590Q identified in [116]
ABCG8 marked ABCB4 together with the
hepatocellular 444A SNP in ABCB11 and
dysfunction D19H in ABCG8
ABCB4, ABCB11 33 cases sequenced Italian Five ABCB4 mutations [43]
identified (L73V, T175A,
N510S, a splice site
mutation and an
insertion causing frame
shift). Six ABCB11
variants identified
(E135K, V284D, D482G,
Q558H, R698H, P731S)
ABCB4, ABCB11, SNP analysis around Caucasian Strong association [35]
ABCC2, ATP8B1, each locus in 563 signals with two SNPs in
NR1H4, FGF19 cases and 642 ABCB11 (rs3815676,
controls. Findings rs7577650) and one in
confirmed in second ABCB4 (rs2109505)
cohort of 227 cases
NK: not known.
a Abstract only available in English.

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Table 2 Genetic studies of ICP; genes that do not influence biliary transport.

Gene or locus name Protein Cohort studied Ethnicity Results and notes Reference

HLA-DPB1 Human leucocyte 26 cases and 30 Chilean No association of disease found [117]
antigen controls with HLA-DPB1 alleles
detected by PCR/SSOH
ApoE Apolipoprotein E 44 cases and 47 Finnish No differences in apoE allele [118]
controls distribution
HLA-DRB1 Human leucocyte 42 cases, 56 controls Chinese Over-representation of DR6 [119]a
antigen allele in patient group,
suggested as ICP susceptibility
locus
ER alpha Estrogen receptor 57 cases, 47 controls Finnish No differences in genotype [90]
alpha distribution of two intronic ER
alpha polymorhphisms
2p13 — 45 cases and 47 Finnish Two markers from the 2p13 [120]
controls region associated with ICP
2p13 — 57 cases, 133 PET Finnish Expanded above study and [121]
cases, 115 controls reported common risk locus for
ICP and PET
HLA-DPA1 Human leucocyte 25 families and 25 Chinese No differences in frequencies [122]a
antigen control families of HLA-DPA1 alleles observed
ER alpha Estrogen receptor 100 cases, 100 Chinese No differences in genotype [123]a
alpha controls frequencies of two intronic
polymorphisms between cases
and controls
ESR2 Estrogen receptor 2 100 cases and 100 Chinese Two RFLPs studied (exons 5 and [124]a
controls 8) and exon 8 polymorphism
associated with risk of ICP
CYP17 and CYP3A4 Cytochrome P450 100 cases and 100 Chinese Promoter polymorphism of [125]a
enzymes involved in controls CYP17 not associated with OC,
estrogen metabolism single CYP3A4 promoter
polymorphism not observed in
this population
HLA-DQA1 Human leucocyte 45 cases, 45 controls Chinese No association between OC and [126]a
antigen plus 18 families and HLA-DQA1; HLA-DQA1*0301
eighteen control proposed as a protective gene
families
HLA-G Human leucocyte 30 cases and Chinese No association with 14bp [127]a
antigen offspring, 30 controls deletion polymorphism of
and offspring HLA-G and ICP
ACTG2 Gamma 2 actin gene 57 cases and 115 Finnish No differences in distribution [128]
controls of ACTG2 intron 1 indel
polymorphism
CYP1A1 Cytochrome P450 100 cases and 100 Chinese Exon 7 I/V polymorphism [129]a
controls proposed to be associated with
ICP
CYP1B1 Cytochrome P450 100 cases and 100 Chinese Polymorphism of exon 2 [130]a
controls proposed to be associated with
ICP
ER beta Estrogen receptor Two groups of 105 Chinese Propose different [131]a
beta cases and 105 (Han and polymorphisms associated with
controls Uygurs) ICP in different ethnic groups
RAGE, GLO I Receptor for 120 controls and 14 Czech No associations detected with [132]
advanced glycation, ICP cases 4 and 1 polymorphism in the
glyoxalase I enzyme two respective genes
Chromosome 2 Over 40 genes in 198 cases and 174 USA and Admixture mapping [51]
candidate region controls Chile
PET: pre-eclampsia.
a Only the abstract of the article is available in English.

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ICP pathophysiology 9

as a mediator of cholestatic pruritus [54], it may be clinically in trophoblast cells and fetal macrophages and hence
useful as a new diagnostic marker [55]. cholestasis may affect the placenta through these pathways
[79]. A dual perfusion ex-vivo model of ICP suggested a
Maternal pathophysiology: reproductive direct effect of taurocholic acid on the placental vascula-
ture, which could contribute to placental dysfunction and
hormone involvement
adverse fetal outcomes [80].
Although the adverse fetal outcomes are the major con-
Maternal metabolic changes are key to a successful preg- cern in the clinical management of ICP, they are poorly
nancy. However, these adaptations can become pathological understood. Evidence is accumulating for bile-acid induced
in genetically susceptible individuals, resulting in gesta- arrhythmias playing a role [81] and placental dysfunction
tional cholestasis or diabetes mellitus. Hence, another caused by bile acid damage (see above) may also contribute
component to understanding the aetiology of ICP is the role [71]. Bile acids may be responsible for increased rates of
of reproductive hormones. With respect to ICP, serum levels preterm labour via prostagladin pathways and may stimulate
of estrogen and progesterone are highest during the third fetal gut motility resulting in meconium-stained amniotic
trimester when the disease usually presents. fluid, although this may be a secondary effect of bile acid
A number of rodent studies have shown a cholestatic toxicity [82,83]. Murine studies also support a role for bile
effect of estrogen administration, with effects seen on acids in disrupting pulmonary surfactant in neonates, poten-
transporter expression and localization [56—59]. Studies of tially leading to the respiratory distress seen in ICP [84].
hepatic expression profiles using microarrays in Fxr knock-
out mice compared to pregnant controls indicated similar Future perspectives
changes, suggesting a desensitization of the FXR pathway
in normal pregnancy and in vitro studies indicate this may Our current understanding of ICP is that the elevated levels
be estrogen-dependent [60]. It was recently demonstrated of reproductive hormones unmask genetic susceptibility in
that FXR can be directly inhibited by 17␤-estradiol-activated some women, resulting in cholestasis and elevated serum
estrogen receptor ␣, resulting in an inhibition of the tran- bile acids.
scription of ABCB11 [61]. A mechanistic understanding of the adverse fetal out-
In addition to estrogen, progesterone is of considerable comes, and the programming effects of in utero exposure
importance in the aetiology of ICP. In particular, a number to high bile acids remain to be established.
of progesterone metabolites have been identified as capable The bacterial content of the gut, the microbiome,
of cross-talk with bile acid signalling pathways, thus having is being increasingly recognised as influencing gut-liver
an impact on the cholestatic phenotype. These metabo- signalling. Pregnancy itself has a profound effect on the
lites are raised in normal pregnancy and further elevated composition of the microbiome [85] and cholestasis in
in ICP (reviewed in [62]). They have been shown to impact rodent models has been demonstrated to have a consider-
hepatocellular bile acid influx by competitively inhibiting able impact [86]. Thus, a role for an altered microbiome
NTCP, and to reduce BSEP-mediated efflux [63,64]. Certain in ICP seems likely. In addition epigenetic alterations,
metabolites also act as partial agonists of FXR, contributing which represent an attractive mechanism for contributing to
to the cholestatic phenotype by desensitising FXR-regulated maternal and fetal pathophysiology have only to date been
pathways [65]. Further, specific metabolites may serve as investigated in a single study of methylation of white blood
early predictive biomarkers as they are elevated prior to cell promotors in ICP women [87]. Further genomic-driven
increased serum bile acids [53]. insights seem likely, as we have now entered the era of whole
genome sequencing (WGS) [36,88]; analysis of an ICP cohort
Placental and fetal pathophysiology using this approach is awaited.
Therapeutic options may also be expanded in the future
During gestation the placenta has a key feto-protective role as a range of new therapies targeted at different compo-
that includes limiting exposure to endobiotic toxic com- nents of the enterohepatic circulation comes to market [89].
pounds such as bile acids [66]. However, the pathways and It is hoped that sophisticated genomic approaches, in com-
signalling involved are considerably different to those in bination with robust evaluation of therapies, will enable a
hepatocytes. Nuclear receptors key to hepatic bile acid more personalised approach to be adopted in the future
homeostasis are expressed at low levels [67] and the key management of ICP.
bile acid transporter ABCB11 is not expressed. It is likely
that another ATP-dependant transporter, ABCG2, mediates Disclosure of interest
placental bile acid efflux [68].
Several studies have reported changes in placental The authors declare that they have no competing interest.
morphology, although these results were not confirmed
in one other study [69—72]. Studies of specific pathways Contribution
have identified a number of changes in cholestatic placen-
tas, including hypoxia-regulated genes [73], urocortin [74], The authors jointly prepared the article.
PPAR-gamma/NF-kappa beta pathways [75] and 11betaHSD2
[76]. A single proteomic analysis and a single expression Acknowledgments
array analysis both produced a range of alterations [77,78]
but as yet a clear pattern of the effect of cholestasis on Research in the Williamson lab is supported by the Wellcome
the placenta has not been established. TGR5 is expressed Trust (P30874), the MRC, the Lauren Page Trust, ICP Support,

Please cite this article in press as: Dixon PH, Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy.
Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2015.12.008
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