Normal Bile Flow: Primary
bile salts are produced in the liver and actively pumped
into the bile cannaliculi system. Bile is transported
through the biliary tree to the intestine where primary
bile acids are converted to secondary bile acids. The
majority of these are reabsorbed and travel back to
the liver forming the enterohepatic circulation. Bile
is important for the disposal of fat soluble waste
products and the absorption of fat soluble vitamins.
Cholestasis refers to the diminished flow of bile formed
by the liver when it reaches a degree of functional
insufficiency. As a result bile constituents accumulate
in the blood and may cause itching. In addition, fat
soluble vitamins (such as vitamin k) are not absorbed
resulting in increased maternal risk of post partum
haemorrhage ( 1, 3)
and fetal intracranial haemorrhage ( 2).
The primary bile acids, especially cholic acid, are
preferentially raised in the serum of those patients
with obstetric cholestasis ( 4).
Bile acids are also raised in the fetal serum, amniotic
fluid and meconium( 5, 6).
The pathogenesis is multifactorial and has yet to
be fully elucidated. Oestrogen and progesterone have
both been implicated in view of the timing of presentation
during pregnancy and resolution post delivery. In addition,
some women experience a similar condition on the oral
contraceptive pill or present with cyclical itching.
Oestrogen is known to have cholestatic properties.
However the total amount of circulating oestrogen and
progesterone in the blood is similar in pregnancies
with or without cholestasis, but there are differences
in their metabolites ( 7).
Therefore cholestasis may be the result of the action
of a metabolite or increased sensitivity to normally
raised levels of oestrogen or progesterone during pregnancy.
Genetics
A family history has been demonstrated in 33-50%
of patients ( 8).
In addition, obstetric cholestasis has been described
in the mothers of children with a subtype of autosomal
recessive progressive familial intrahepatic cholestasis
(PFIC) ( 9).
The mothers are heterozygous for a mutation in the
human multidrug resistance 3 (MDR3) gene, whilst their
children are homozygous. This gene codes for a glycoprotein
involved in the biliary secretion of phospholipids.
Thus the mutation results in alterations in the bile
composition. Heterozygosity for this mutation has also
been found in a subgroup of women with no family history
of PFIC but raised gamma-glutamyl transpeptidase ( 10).
This may represent a further subgroup of women with
OC and raised GGT secondary to a genetic mutation.
Proposed Mechanism for Fetal Compromise
Several mechanisms have been proposed including a
direct toxic effect on the fetus or a vasospastic effect
on the placental circulation ( 11).
A recent study has demonstrated that addition of the
primary bile acid taurocholate causes a decrease in
the rate of contraction of rat cardiomyocytes in vitro
( 12).
Addition of the bile acid to a network of such cells
caused a further decrease in contractility and disruption
to the integrity of the network. This could explain
the development of fetal dysrrhythmia and sudden intra-uterine
death.
References
1.Reid R, Ivey KJ, Rencoret RH, Storey B. Fetal complications
of obstetric cholestasis. Br Med Journal 1976;1:870-2, Abstract
2. Fisk NM, Storey GNB. Fetal outcome in obstetric
cholestasis. Br J Obstet Gynaecol 1988; 95:1137-43, Abstract
3. Johnston WG, Baskett TF. Obstetric cholestasis.
A 14 year review. Am J Obstet Gynaecol 1979;133:299-301, Abstract
4.Bacq Y,Myara A, Brechot MC, Hamon C, Studer E, Trivin
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Gynecology, & Reproductive Biology.1991; 42(3):211-5, Abstract
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fetal death in obstetric cholestasis. Clinical Science.2001;
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