Journal of Hepatology 2000; 33: 1012–1021
Printed in Denmark ¡ All rights reserved
Munksgaard ¡ Copenhagen
Copyright C European Association
for the Study of the Liver 2000
Journal of Hepatology
Intrahepatic cholestasis of pregnancy: molecular pathogenesis,
diagnosis and management
Frank Lammert, Hanns-Ulrich Marschall1, Anna Glantz2and Siegfried Matern
Department of Internal Medicine III, Aachen University of Technology – RWTH, Aachen, Germany,1Karolinska Institutet, Department of
Medicine, Division of Gastroenterology and Hepatology, Huddinge University Hospital, Stockholm, and2Department of Obstetrics and Gynecology,
Sahlgren’s University Hospital, East, Göteborg, Sweden
hereditary and acquired liver diseases. Intrahepatic
cholestasis of pregnancy (ICP) is a reversible form of
cholestasis in late pregnancy, persisting until delivery.
The first case of unexplained pruritus associated with
visible jaundice appearing in the last trimester of preg-
nancy and clearing shortly after delivery was reported
in 1883 (1). The disease remained unnoticed and un-
named until the mid-1950s when the detailed clinical
features were described by several Scandinavian clini-
cians [for a review, see (2)]. Familial clustering and en-
demic occurrence of cholestasis of pregnancy strongly
indicated a genetic basis. Recent progress in molecular
dissection of bile secretion has led to the identification
of several gene defects that cause cholestatic liver dis-
eases. These genes are now being tested as candidate
genes predisposing to cholestasis of pregnancy.
The incidence of ICP in Europe is approximately 10
to 150 per 10 000 pregnancies (Table 1). For pregnant
women with cholestasis, quality of life can be impaired
by itching, jaundice and fat malabsorption, but the
prognosis for the mother is good. In contrast, ICP is a
condition with possible lethal outcome for the unborn
child if not handled with care. The major consequences
of ICP are premature births in 19 to 60% of affected
pregnancies (3–5), a high rate of intrapartal fetal dis-
tress in 22 to 33% of deliveries (6,7), and stillbirths in
1 to 2% of ICP pregnancies (4,5,8–10). In spite of these
substantial risks, ICP is often neglected and treated ex-
pectantly, even in obstetric centers. It is therefore es-
, or impaired bile flow, is one of the
most common and devastating manifestations of
Correspondence: Hanns-Ulrich Marschall, Karolinska In-
stitutet, Department of Medicine, Division of Gastro-
enterology and Hepatology, Huddinge University Hospi-
tal K63, S-141 86 Stockholm, Sweden.
Tel: 46 8 58582492. Fax: 46 8 58582335.
sential to increase interest in and knowledge of the dis-
ease, and to find a safe medical treatment that im-
proves fetal outcome.
Hormonal factors: estrogens
Genetic predisposition and hormonal factors play key
roles in the pathogenesis of ICP. Evidence for a pri-
mary role of hormonal factors in ICP was provided by
the following observations (2):
O The disease starts in the last trimester which is the
period of the highest hormone concentrations.
O Twin pregnancies display both a higher incidence of
ICP and more pronounced rises in hormone levels.
Incidence of intrahepatic cholestasis of pregnancy (n per 10 000 preg-
Country Incidence Time of surveyReference
Cholestasis of pregnancy
O ICP resolves promptly after delivery, when levels of
placental hormones return to normal.
O In further pregnancies, ICP recurs in 45–70% of the
Estrogens, in particular glucuronides like estradiol-
17b-D-glucuronide, were found to be cholestastic in
animal studies where they diminished the uptake of
bile acids at the basolateral membrane of hepatocytes.
An increased permeability of tight junctions (11) and
a decreased fluidity of the sinusoidal membrane (12)
have been suggested as underlying mechanisms. De-
creased membrane fluidity lowers the Naπ/Kπ-ATPase
activity (13), which results in a reduction of the sodium
gradient that is necessary for the sodium-dependent
bile acid uptake into the hepatocyte. However, these
mechanisms may not be primary but secondary effects
due to cholestasis (13,14).
eral proteins responsible for the specific transport of the
main components of bile, i.e. bile acids, other organic
anions, phospholipids such as phosphatidylcholine
(lecithin), and cholesterol. These translocating proteins
are localized at the basolateral and canalicular mem-
branes that are functionally and biophysically distinct
domains of the hepatocyte plasma membrane (Fig. 1).
eral bile acid transport proteins (Naπ-dependent tauro-
cholate cotransporting polypeptide, NTCP; organic an-
ion cotransporting polypeptides, OATP) occurs at the
transcriptional level (15). Biliary excretion of estradiol-
17b-D-glucuronide is performed by the canalicular
multispecific conjugate export pump (multidrug resis-
tance related protein, MRP2) which causes a trans-inhi-
bition of the canalicular bile acid export pump (BSEP)
(16). Furthermore, estradiol-17b-D-glucuronide sup-
presses the expression of MRP2 at the posttranscrip-
tional level (17).
Hepatic biotransformation of the major estrogen in
pregnancy, estradiol, includes sulfation and glucuron-
idation (Fig. 1). These conjugation reactions are typi-
cal phase II detoxification reactions, which help to
diminish the cholestatic effect of estrogens (18). How-
ever, the estrogen conjugate that increases most in
pregnancy, estriol-16a-D-glucuronide (19), was itself
found to be cholestastic, at least in animals (20). Beside
decreased biliary excretion of estrogen metabolites, im-
paired hepatic sulfation was observed in ICP patients,
using a xenobiotic surrogate compound (21).
Hormonal factors: progesterones
In the pathogenesis of ICP, progesterone metabolites
seem to play an even more important role than estro-
gens (22). An early observation described the develop-
ment of ICP-related symptoms after the administration
of progesterone in a woman with a history of ICP (23),
and recent studies showed that progesterone treatment
during the third trimester was associated with ICP
(24). The profile of progesterone metabolites in plasma
from patients with ICP is markedly different from that
seen in normal pregnancy (25,26). It has been dis-
cussed whether the changes can be explained on the
basis of cholestasis alone or by specific derangements
of the reductive metabolism of progesterone or the sulf-
ation of its metabolites. It is noteworthy that pregnant
women with cholestasis due to viral hepatitis have a
normal profile of steroid sulfates in blood (27), sug-
gesting that the typical pattern of sulfated progester-
one metabolites may only be attributable to ICP.
During pregnancy, 250 to 500 mg of progesterone
are synthesized in the placenta per day. In the liver,
progesterone is reduced to pregnanolone and pregnan-
ediol (Fig. 1). Four different isomers, 3a/3b and 5a/5b,
are formed, which are further metabolized by hydroxyl-
ation and conjugation with sulfate and glucuronic
acid. Mono- or disulfated progesterone metabolites are
the most prevalent steroids during pregnancy with
plasma levels of 10 to 15 mmol/l (28). These compounds
are substantially increased in patients with ICP, in par-
ticular the 3a,5a-isomers (25,29). The different ratio of
3a- and 3b-hydroxy steroids is most characteristic for
ICP (30). Both biliary and fecal excretion of sulfated
and glucuronidated progesterone metabolites are de-
creased in patients with ICP (31,32). Substantial
amounts of sulfated progesterone metabolites in urine
of pregnant women are additionally conjugated with
N-acetylglucosamine (GlcNAc) (30,33). The formation
of these metabolites is selective for 7b-hydroxy bile
acids such as UDCA (34), which is used to treat ICP
(see below). GlcNAc-conjugates are also the major uri-
nary metabolites of UDCA in health (34,35) and cho-
lestatic liver diseases (36) including ICP (30).
The incidence of ICP shows striking geographic and
ethnic differences (Table 1). ICP is most common in
Scandinavia and South America. The highest rates of
ICP are detected in Chile (16%), especially in women
with overt Araucanian Indian descent (28%) (37). The
heterogeneous incidence in women of different ethnic
origin, familial clustering as documented in several
pedigree studies (38,39), and higher incidences in
mothers and sisters of patients with ICP (40–42)
clearly indicate a genetic predisposition for ICP. A high
prevalence of the HLA haplotype Aw31B8 in patients
with ICP was found in one kindred (38), but could not
F. Lammert et al.
Fig. 1. Schematic diagram of the hepatic metabolism of hormonal factors that contribute to intrahepatic cholestasis of
pregnancy (ICP). Hepatic estrogen conjugates inhibit bile salt uptake via the Naπ-dependent taurocholate cotransporting
polypeptide (NTCP) and organic anion cotransporting polypeptides (OATP). Estrogen-glucuronides are excreted via the
multidrug resistance associated protein 2 (MRP2) into bile, where they trans-inhibit the bile salt export pump (BSEP). Key
enzymes of the hepatic progesterone metabolism include D4-3-oxosteroid-5b(a)-reductase and 3a/b-hydroxysteroid-dehydro-
genase, which convert progesterone to pregnanolone and pregnanediol. These metabolites are conjugated with sulfate, glucu-
ronic acid, and/or N-acetylglucosamine. The export pump for sulfated progesterone metabolites is unknown but might be
related to multidrug resistance associated proteins (MRP). Progesterone binds to and modulates the activity of the phosphati-
dylcholine translocase MDR3.
be confirmed in a later study (42). Thus, the genetic
base of ICP is still under investigation.
Current research on the pathogenesis of ICP focuses
on two major questions: Is there a defect in transport
proteins disabling the biliary excretion of physiologic-
ally occurring metabolites in pregnancy or do quanti-
tatively or qualitatively abnormal metabolites inhibit
otherwise normally working transport proteins? The
increased amount of sulfated progesterone metabolites
in plasma could, for example, saturate the maximal
transport capacity of dedicated transport proteins. The
search for a genetically defined aberration of structure
or function of hepatic transport proteins in patients
with ICP is motivated by recent progress in the molecu-
lar characterization of other cholestatic disorders (43).
In 1998, mutations in genes encoding biliary trans-
port proteins were identified in patients with progress-
ive familial intrahepatic cholestasis (PFIC) [for reviews
see (44,45)]. The first mutations were found in the gene
FIC1 (Familial intrahepatic cholestasis 1). The defect
is prevalent in two cholestatic disorders with quite dif-
ferent prognosis (46): patients with Byler’s syndrome
(PFIC type 1) develop liver cirrhosis in childhood,
whereas in many patients with benign recurrent in-
trahepatic cholestasis (BRIC) no major complications
occur. The gene FIC1 codes a P-type-ATPase that is
expressed in the ileum and in large cholangiocytes. The
protein may function as an aminophospholipid trans-
locase and is supposed to play an important role in the
enterohepatic circulation of bile acids.
In patients with PFIC type 2, mutations of the he-
patic canalicular bile acid translocase (BSEP) have
been identified (47). Patients with PFIC type 3 display
mutations of the gene encoding the canalicular phos-
phatidylcholine translocase (Multidrug resistance gene
3, MDR3) (48). In contrast to other types of PFIC,
patients with PFIC type 3 are characterized by elevated
serum g-glutamyl transferase (g-GT) levels, which are
due to bile acid toxicity in phosphatidylcholine de-
Cholestasis of pregnancy
In mothers of patients with PFIC or BRIC, a higher
incidence of ICP has been observed (49–51). This in-
dicates that heterozygote mutations of hepatobiliary
transport proteins predispose to ICP. This hypothesis
is supported by the finding that in the family of a PFIC
type 3 patient, six women with a history of ICP were
heterozygous for the same deletion (1712delT) in the
MDR3 gene (52). In addition, DNA sequence analysis
identified one woman with ICP and raised serum
g-GT, but with no known family history of PFIC, who
displayed a missense mutation (C546A); fluorescence
activated cell sorting and Western analysis demon-
strated disruption of protein trafficking with a sub-
sequent lack of functional protein at the cell surface
(53). However, the most prevalent defects in the ma-
jority of ICP patients remain to be defined. The close
link between genetic and hormonal factors is corrobo-
rated by the finding that progesterone binds to and
modulates the activity of MDR-translocases such as
the phosphatidylcholin translocase MDR3 (54).
Some characteristics of ICP suggest that in addition
to hormonal and genetic factors, environmental and
alimentary factors may increase the risk for ICP in pre-
disposed women. This is indicated by the decline of
ICP prevalence rates in Chile during the last decades
(Table 1), and the fact that ICP recurs in less than 70%
of pregnancies in multiparous women. It was also re-
ported from Sweden, Finland and Chile, that the inci-
dence of ICP is higher in winter than in summer
(9,55,56). Therefore, exogenous factors may superim-
pose on the genetic predisposition and lead to manifes-
tation of the disease. Some studies linked ICP to low
serum selenium (Se) levels (56,57). Se acts as a cofactor
of several enzymes in the oxidative metabolism in the
liver but the role of Se in bile secretion has yet to be
The pathogenesis of stillbirths in ICP is not fully
understood. Autopsies show signs of acute, lethal an-
oxia with petechial bleeding in pleura, pericard and ad-
renal glands, but no signs of chronic anoxia (4,10,58).
In ICP pregnancies there is a major increase in the inci-
dence of meconium-stained amniotic fluid (6,7,58),
with stillborns often lying in heavily stained fluid (4,5).
However, fetuses of women with ICP have adequate
birthweights for gestational age and normal Doppler
umbilical artery velocimetry (59), suggesting that
chronic placental insufficiency is not the primary cause
of fetal death. Infusion of cholic acid to fetal sheep
increases the incidence of meconium passage, indi-
cating stimulation of colonic motility by bile acids (60).
In experimental models, it has been shown that mec-
onium can cause acute umbilical vein constriction and
lead to a reduction in umbilical flow (61,62).
During ICP there is an increased flux of bile acids
from the mother to the fetus, as indicated by increased
bile acid levels in amniotic fluid (63,64), cord plasma
samples (65), and meconium (66). Because the high bile
salt levels were found to be associated with more fre-
quent occurrence of fetal distress (65), this might be of
great relevance for fetal prognosis, although the patho-
physiological mechanisms have yet to be defined. Bile
acids have been shown to induce vasoconstriction of
human placental chorionic veins in vitro (67).
Fetal bile acid balance is dependent on the placental
transfer capacity for bile acids. Recently, in vesicle
preparations of the basal (fetal) and apical (maternal)
trophoblast membranes from patients with ICP, a
diminished placental transport of bile acids was ob-
served. This is supposed to result in decreased fetal
elimination and a retention of toxic bile acids in the
In the past, icterus was believed to be the major clinical
finding in ICP. However, the most common symptom
is severe pruritus, which most typically appears in the
third trimester and starts in palms and soles. In 10%
of the patients, pruritus develops in the first trimester
and 25% of the patients present with pruritus in the
second trimester (70). The pruritus is generally more
severe at night and can lead to considerable discomfort
for the patients. Only 10% of the patients with pruritus
develop icterus (5). Thus, the old term pruritus grav-
idarum designates the mild course of ICP, whereas ic-
terus gravidarum describes the aggravated course of
ICP. Icterus without pruritus is rare. In most patients,
pruritus and icterus disappear promptly after delivery,
within 1–2 days; sometimes pruritus persists for 1–2
weeks. However, some cases with a protracted course
of the disease have been reported (71). Four Puerto
Rican sisters had recurrent prolonged cholestasis of
pregnancy, which was followed by periportal fibrosis or
cirrhosis but was most likely not identical to ‘‘classical’’
ICP (72). This study indicates that patients with pro-
longed cholestasis during pregnancy should be moni-
tored for evidence of chronic liver disease, should be
counseled on the risks of disease recurrence and pro-
gression in future pregnancies, and should inform fam-
ily members at risk of the disease and its possible
ICP may rarely cause steatorrhea with decreased ab-
sorption of fat-soluble vitamins and weight loss. In
F. Lammert et al.
cases with severe steatorrhea, increased intra- and
postpartum hemorrhage may occur if the patient is not
supplemented with adequate doses of vitamin K before
delivery. Abdominal pain or fever are not observed,
unless ICP is associated with other diseases like uri-
nary tract infection.
ICP is associated with a predisposition for chol-
esterol gallstones, and the incidence of ICP is higher
among gallstone patients (73–75). Primigravidae with
ICP have a 2.7-fold increased risk for gallstones com-
pared to pregnant women without cholestasis (74).
Both fasting and postprandial gallbladder volumes are
increased in ICP (76,77). This increase indicates gall-
bladder hypomotility, which is believed to result from
cholesterol absorption by the gallbladder wall (78).
Interestingly, the ICP candidate genes discussed above
have also been established as genetic determinants for
cholesterol gallstone disease in animal models (79).
Liver function tests are to be performed in every preg-
nant woman who experiences pruritus. The increase of
serum bile acids in combination with typical pruritus
is highly suggestive of the diagnosis of ICP.
Among standard liver tests, alanine transaminase
(ALT) is a very sensitive parameter for ICP (3). Serum
transaminase levels are normal until delivery in healthy
pregnancies and therefore, any rise should alert and
lead to further tests. ALT is released into the blood in
increasing amounts when the liver cell is damaged (80).
It has been reported that 20–60% of women with pru-
ritus and elevated serum bile acid levels have 2–10-fold
rises in transaminases (5,81,82), but there is poor cor-
relation between the levels of serum bile acids and
The most sensitive indicator for ICP is a rise of serum
bile acid levels (Table 2). In healthy pregnancies, total
serum bile acids are slightly higher in pregnant (6.6∫0.3
mmol/l) than in non-pregnant woman (5.7∫0.4 mmol/l)
(85), and levels up to 11.0 are accepted as normal in late
gestation (86). It is important to emphasize that the av-
Laboratory findings in intrahepatic cholestasis of pregnancy (135)
Test Number of patients Percent of women with
Average valueMaximum value
2.2∫1.6 mkat/l (131∫96 U/l)
2.0∫0.9 mkat/l (119∫51 U/l)
2.4∫1.1 mkat/l (146∫66 U/l)
17 mmol/l (1.0 mg/dl)
17.2 mkat/l (1030 U/l)
12.3 mkat/l (736 U/l)
12.5 mkat/l (750 U/l)
315 mmol/l (8.4 mg/dl)
erage value for total serum bile acids in ICP patients in
Table 2 is a consequence of cases with more serious ill-
ness; in fact, a number of patients with markedly lower
concentrations have been reported (3,10). In ICP, gly-
cine- or taurine-conjugated bile acids, in particular
creased cholic acid/chenodeoxycholic acid (CA/CDCA)
ratio of approximately 4:1 (89). In normal pregnancies
of the same gestational age as well as in non-pregnant
women, the CA/CDCA-ratio is ?1.5 (89). The abnor-
mally high ratio in ICP patients might reflect the fact
that the less polar bile acid CDCA is preferably sulfated
and excreted in the urine. Both in women with ICP and
in women with healthy pregnancies. the serum bile acid
composition shows a marked predominance of CA and
to bile of non-pregnant women (90). The measurement
of bile acid concentrations in serum is particularly help-
ful in pregnant women with pruritus but normal trans-
aminases. The urinary bile acid excretion is increased
approximately 10-fold during ICP (30).
Total serum alkaline phosphatase (ALP) levels rise
slightly in normal pregnancies due to high production
of placental and bone isoenzymes (91). ALP levels are
usually elevated in ICP patients (Table 2), but are of
poor diagnostic value. g-GT, which is generally lower
in late pregnancy, is usually normal or slightly elevated
in ICP. If g-GT levels are high, mutations in the MDR3
gene are suspected, but not routinely tested to date.
Hyperbilirubinemia, up to 100 mmol/l (5 mg/dl) is only
detected in 10–20% of the cases (Table 2). In urine,
bilirubin and urobilinogen can be tested positive.
Serum protein electrophoresis reveals slightly de-
creased albumin, whereas a2-globulins are moderately
and b-globulins appreciably increased (92). The in-
crease of LDL-cholesterol and triglycerides, which is
observed during pregnancy, is more pronounced in
cholestatic patients including ICP, whereas HDL-chol-
esterol may decrease (70). Cholestasis is associated
with the appearance of the abnormal lipoprotein X
(LpX) in plasma. LpX are 40–100-nm vesicles, which
Cholestasis of pregnancy
contain unesterified (free) cholesterol. Using mice with
a disrupted Mdr2 gene (murine homolog of MDR3),
Oude Elferink et al. (93) demonstrated that the appear-
ance of LpX is dependent on the presence of the cana-
licular translocator for phosphatidylcholine (MDR2)
and that abnormal excretion of biliary vesicles into
blood occurs during cholestasis.
An upper abdominal ultrasound is considered in
ICP patients with abdominal symptoms or puzzling
laboratory controls. Liver biopsy in general is un-
necessary. Histology would show mild focal irregular
intrahepatic cholestasis with bile plugs in the canaliculi
and small amounts of bile pigment in centrilobular
hepatocytes and macrophages. Necrosis or inflam-
mation is absent. Electron microscopy revealed dilated
bile canaliculi and loss of microvilli as well as mito-
chondrial alterations, including enlargement, irregular
shape, and lamellar inclusions (94).
The main differential diagnoses of pruritus of ICP
without icterus are skin diseases, allergic reactions and
pruritus related to abdominal striae. Only 0.07% of all
pregnant woman develop visible icterus (95). The clini-
cian distinguishes icterus in graviditate, the coincidence
of icterus and pregnancy, from icterus e graviditate as a
specific complication of pregnancy (Table 3). The acute
fatty liver of pregnancy presents with transaminases up
to 12 mkat/l (500 U/l), severe hypoglycemia, hepatic
encephalopathy, and beginning disseminated intravas-
cular coagulation. Pre-eclampsia is characterized by
hypertension and proteinuria, and severe forms can be
complicated by the HELLP-syndrome, which is de-
fined by hemolysis, elevated liver enzymes, and low
platelet count. The rise of transaminases is lower than
Differential diagnosis of intrahepatic cholestasis of pregnancy (ICP)
with jaundice (95)
Etiology Prevalence (%)
Icterus e graviditate
Acute fatty liver of pregnancy
Icterus in gravididate
Bile duct obstruction
in viral hepatitis and bilirubin is usually normal. In
patients with high transaminases and/or high bilirubin,
acute viral hepatitis, choledocholithiasis and toxic
hepatitis are to be excluded. A high and rapid increase
of transaminases favors acute viral or toxic hepatitis.
Bile duct obstruction causes an increase in g-GT and
ALP, and abdominal sonography confirms the diag-
nosis. If cholestasis and elevated transaminases persist
for more than 4 weeks after delivery, chronic liver dis-
eases like primary biliary cirrhosis have to be ruled
out by testing for antimitochondrial antibodies (AMA)
and liver biopsy.
ICP is a fairly common disease with a high impact on
fetal morbidity and mortality, and it is also a condition
of great discomfort for the patients. Obstetric manage-
ment of patients with ICP varies widely over the world.
In spite of numerous reports of increased fetal risk
(4,5,96) many obstetric clinics still choose to manage
ICP pregnancies expectantly. Many different protocols
for intensified surveillance have been proposed. It has
been shown that a regimen including weekly fetal car-
diotocographic (CTG) monitoring from the 34th week
of gestation and induction of labor in the 38th week of
gestation in mild cases, and in the 36th week of ges-
tation in severe cases can reduce perinatal mortality to
control levels (5). Another group (4) reported reduc-
tion of perinatal mortality by active management (in-
cluding amnioscopy and generous induction of labor)
to one third, compared to expectant management with-
out fetal monitoring (4). The authors point out that
the protocol still does not totally eliminate the risk of
acute fetal death before onset of labor.
To date no randomized trials have been conducted
to investigate the optimal surveillance level at a cost-
benefit basis. Most authors agree that weekly CTG
registrations are valuable, at least from the 34th week
of gestation on. Weekly assessments of serum bile
acids, transaminases, and bilirubin should be con-
ducted. In severe cases or if the patient suffers from
steatorrhea, control of prothrombin time should be
considered. Obstetric management consists of weighing
the risk of premature delivery against the risk of sud-
den death in utero. In addition, it has to be considered
that induction of labor is associated with a higher fre-
quency of complications such as operative deliveries
compared to spontaneous labor. Since fetal prognosis
correlates with disease severity (10,55,58), the aim of
treatment should be reduction of bile acids in order to
prolong the pregnancy and reduce both fetal risk and
Frequencies of abortions and malformations are not
F. Lammert et al.
increased in ICP. Birthweights are adequate for ges-
tational age. Breastfeeding is not contraindicated. Pa-
tients with a history of ICP may use low-dose oral con-
traceptives after normalization of liver function tests,
provided they are instructed to stop medication if pru-
ritus and cholestasis recur.
Antihistamines, anion exchange resins and phenobar-
bital are given to remove putative peripheral pruritog-
ens or to reverse their effects on empiric grounds (97).
These therapeutic options have not received wide ac-
ceptance for treatment of ICP patients because of their
ambiguous efficacy or side effects. Anion exchange
resins such as colestipol or colestyramine bind bile
acids and interrupt their enterohepatic circulation.
They should therefore be given separately from urso-
deoxycholic acid (UDCA, see below) (98). Since both
ICP and colestyramine may independently lead to vit-
amin K deficiency, it is important that ICP patients
who are treated with anion resins receive parenteral
substitution of fat-soluble vitamins (A, D, and K). Be-
cause of the risks of antepartal fetal hemorrhage (99)
and intra- and postpartal maternal bleedings, and the
minor effect on pruritus, colestyramine is nowadays
not considered first-line therapy for ICP.
S-adenosylmethionine (SAM) improves cholestasis
in the ethinylestradiol-treated rat (14). It is a precursor
of glutathione and, as a universal methyl group donor,
involved in the hepatic synthesis of phosphatidylcho-
line. Thus, SAM has been proposed to influence not
only the composition and fluidity of hepatocyte plasma
membranes, but also methylation and biliary excretion
of hormone metabolites. In two Italian ICP studies,
daily intravenous application of 800 mg SAM for 20
days (100) or oral application of 1600 mg SAM (101)
resulted in significant decreases of pruritus, bilirubin,
and ALT. However, 900 mg SAM in daily intravenous
infusions were without effect in a double-blind, pla-
cebo-controlled study in 9 Chilean patients with mod-
erate or severe ICP (102). In conclusion, the role of
SAM in ICP treatment is still a matter of debate.
Phenobarbital was once thought to be a therapeutic
alternative for ICP, but it relieved pruritus in only 50%
of the patients and showed no beneficial effects on liver
parameters (103,104). Dexamethasone and UDCA are
treatment options being currently evaluated. Dexa-
methasone inhibits the feto-placental hormone syn-
thesis, and a single study demonstrated significant im-
provement of pruritus, bile acids and ALT in 10 pa-
tients, who were treated with dexamethasone at an ini-
tial dose of 12 mg four times daily for 7 days with
subsequent dose tapering over 3 days (105).
UDCA, a naturally occurring hydrophilic bile acid
(106), improves clinical and biochemical indices in a
variety of cholestatic liver diseases (107). It is now-
adays considered as the first-line treatment option for
patients with primary biliary cirrhosis (PBC), because
the results from the combined analysis of the three
largest randomized clinical trials of UDCA in PBC in-
dicate that UDCA improves survival free of liver trans-
plantation (108). These results are under intense dis-
cussion (109–111). The mechanisms of action of
UDCA are still under debate. There is evidence that
the hydrophilic UDCA protects against injury to bile
ducts by hydrophobic bile acids and stimulates the ex-
cretion of these and other potentially hepatotoxic com-
Based on the positive experiences in PBC, UDCA
has been used for the treatment for ICP as well. In a
study with 20 ICP patients, UDCA at a dose of 450
mg/day was more effective in relieving itching and
lowering serum bile acids than SAM at a dose of 1000
mg/day (112). The beneficial effects of UDCA have
been confirmed in two small randomized double-blind
placebo-controlled trials in 16 patients with ICP
(113,114). At a dose of 600–1000 mg per day, signifi-
cant improvements in pruritus, bilirubin and transam-
inases were observed.
In ICP patients, UDCA normalizes the increased
CA/CDCA ratio (115,116) and reduces plasma concen-
trations as well as urinary excretion rates of sulfated
steroid metabolites (115). Furthermore, administration
of UDCA both restores the impaired bile acid trans-
port across the trophoblast in ICP (68) and decreases
the delivery of bile acids to the fetus (63,116–121), re-
presenting a valuable contribution to fetal well-being
and outcome (114).
UDCA has virtually no side-effects except for mild
diarrhea in rare cases. Up to now, no adverse effects
on the fetus have been reported. Because the start of
treatment with UDCA is usually delayed until the third
trimester, the risk of teratogenicity is further mini-
mized. Because UDCA has not yet been approved for
ICP treatment, results of future larger randomized,
controlled UDCA trials in ICP patients are eagerly
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