Research
What is known so far
Research into the causes of OC has been ongoing for over 30 years. However, researchers are still a long way from fully understanding the condition. Below is a brief summary of the key findings of OC research.
Genetic variation
It has been shown that in some women there is variation in some genes responsible for the transport of molecules in the liver. These molecules are involved in the formation of bile, and when there is variation they work less efficiently. This means that there is a build up of bile acids in the blood, resulting in the symptoms of OC. Although this has been a huge focus for research in OC we are still a long way from explaining all cases by means of genetic variation and the work continues today.
Bile acids
A blood bile acid level of over 40 micromol/L at any time during a pregnancy appears to be associated an increased risk of complications for your baby, including fetal distress and premature labour. It should be noted that the most recent large Swedish study measured fasting bile acid levels. In the UK, random blood samples are most commonly taken and the effect of food on bile acid level has not fully been established. More work is needed in this area to see if there is a similar correlation between random bile acid level and risk to the baby.
UDCA
There is some evidence that UDCA treatment not only relieves the symptoms experienced by the mother, but may also offer some protection against the harmful effects of bile acids for the baby. These findings need to be confirmed in studies with larger numbers of women, and the mechanism established.
Bile acids and fetal complications
There are several ways in which bile acids may harm your baby. These include abnormal heart rhythms, abnormal contraction of the veins supplying your baby with nutrients, increased sensitivity of the uterus to hormones which may trigger labour, increased sensitivity of the baby's intestines to bile acids, which may cause passage of meconium. Again, more research is needed in this area as some pregnancies seem to be at higher risk than others.
Research groups
The London group
For the past 10 years, a team in London, based at Imperial College and led by Professor Catherine Williamson has been trying to understand the genetic causes of OC. Currently there are several projects continuing this aspect of the work, and also others trying to further understand the effects of bile acids on your baby’s heart.
Reproduced with kind permission of Action Medical Research
The London group is comprised of the people listed below. You can read about the work of Professor Catherine Williamson and Dr Saskia van Mil by clicking on their names.
Post-Doctoral Researchers
- Dr Peter Dixon
- Dr Shadi Abu-Hayyeh
- Dr Georgia Papacleovoulou
PhD Students
- Dominic Lawrance
- Dr Marcus Martineau
- Dr Erum Khan
- Suzan Jeffries
- Jenny Chambers
- Victoria Geenes – will be returning to medical school to complete her final year
- Alexandra Milona – will continue to work in the group for a while
- Bryn Owen – will be taking up a new post in the USA
- Hamimah Sheikh Abdul Khadir
Professor Catherine Williamson
Our group has studied different aspects of obstetric cholestasis over the past 10 years. We are particularly interested in why some women develop the condition. This is likely to be explained by genetic factors and also by the way the liver responds to raised levels of female hormones in pregnancy.
We have identified genetic variation in several genes that influence the way the liver controls bile acid levels. A small number of genetic abnormalities cause women to be very likely to develop OC when they are pregnant. However, in most cases there will not be just one genetic abnormality that makes them likely to develop the condition. Therefore we are also adopting more sophisticated approaches to the genetic analysis of the condition, and we are trying to identify groups of genes that can make pregnant women susceptible to cholestasis.
In addition to studying genetic causes of OC we are interested in how raised female hormones in pregnancy influence the liver and cause cholestasis. We are using several experimental models of cholestasis in pregnancy to study how oestrogen, progesterone and their metabolites influence the way the liver controls bile acid levels in the blood.
We are also studying the reasons that the babies of women with the disease can become unwell and, in severe cases, be stillborn. This part of the work includes studies of the placenta and also experiments to establish how bile acids may affect the heart of the unborn baby. We are studying how different drugs may prevent bile acid-induced damage to fetal tissues.
Work performed by several groups has shown that the drug ursodeoxycholic acid improves the symptoms and liver test abnormalities of women with OC. We are performing studies to try to understand whether this drug also improves the outlook for the baby. These include laboratory studies and a clinical trial. This trial is a collaborative study which is coordinated by Nottingham University and has several collaborating hospitals, including Queen Charlotte’s Hospital and St Mary’s Hospital from Imperial College London, St Thomas’ Hospital, Sunderland Hospital, Kings Mill, Mansfield and Heartlands/Good Hope Hospital, Birmingham.
We are currently starting a new project to establish whether the presence of cholestasis during pregnancy will influence the mother’s subsequent health or that of her children.
Our work has used a considerable number of samples from women who have had OC and their relatives. Several women have also given their time to raise funds for our work. We are very grateful to all the women who have helped us and hope that this work will improve the health of women with OC and their babies in the future.
The Utrecht Group
Bile homeostasis
Each day, approximately 500 mg of bile acids are synthesized
from
cholesterol in
the adult human liver. Newly synthesized bile acids are conjugated with
either
glycine or taurine and subsequently secreted into bile and stored in
the
gallbladder. Biliary secretion of bile salts against a concentration
gradient
requires the hydrolysis of ATP and this process provides the driving
force for
bile flow. Because of detergent properties, bile acids are inherently
cytotoxic,
and hence it is important that intracellular levels of bile acids are
tightly
regulated. This is largely accomplished by transcriptional regulation
of genes
encoding proteins involved in bile acid synthesis and transport.
Cholestasis, or
impaired bile flow, is one of the most common and devastating
manifestations of
liver disease. Cholestasis is clinically characterized by elevated
plasma
concentrations of biliary constituents, resulting in jaundice,
malabsorption of
fats and fat-soluble vitamins and, in many cases, progressive liver
damage. Both
acquired and hereditary forms of cholestasis have been described.
About me
I
am a Dutch scientist who worked in Catherine Williamson’s group at
Imperial
College London. Over the course of my BSc project, PhD and post-doc
position, I
have cultivated a strong research interest in bile acid-related
physiology, with
particular reference to cholestasis. During my PhD programme in the
University
Medical Center in Utrecht, The Netherlands, I focussed on elucidating
the
genetic defect in two cholestatic disorders occurring in young
childhood, BRIC
and PFIC. I was involved in the study that demonstrated that mutations
in FIC1,
an aminophospholipid transporter, were causative for a subgroup of
these
patients. Following up from this study, we identified a second form of
BRIC
associated with mutations in the bile salt export pump (BSEP).
Furthermore, I
investigated the subcellular expression pattern of FIC1 in the liver.
We
revealed FIC1 localisation at apical membranes of cholangiocytes and
hepatocytes
and demonstrated that FIC1 is expressed in a tissue specific and
developmentally-regulated fashion at the apical membranes of epithelial
cells of
the gastrointestinal tract. During my PhD project I became interested
in the
regulation of bile acid homeostasis by nuclear hormone receptors, and
therefore
approached Catherine Williamson to explore new ideas about the role of
nuclear
receptors and endocrine regulation of transporters in bile homeostasis.
Functional FXR variants associated with ICP
Because of the intrinsic toxicity of bile acids, bile acid synthesis
and
transport are tightly regulated. It has recently become apparent that
members of
the nuclear receptor family of transcription factors are key regulators
of these
physiological processes1. The transcription
factor FXR (farnesoid X receptor)
functions as a critical sensor of bile acid levels in the enterohepatic
circulation and modulates bile homeostasis by binding to DNA response
elements
in promoter regions of target genes. Thus, FXR protects the body from
the
deleterious effect of bile acid overload by decreasing their endogenous
synthesis and by accelerating bile acid biotransformation and excretion
into
bile, thereby preventing the occurrence of cholestasis. Synthetic FXR
ligands
may therefore represent a promising therapy for cholestasis. During my
post-doc
at Imperial College with Catherine Williamson, I hypothesised that FXR
mutations
cause ICP. Indeed, we identified four heterozygous variants in FXR in
92 women
with ICP. Case-control studies of these variants in two independent
cohorts of
ICP patients and controls, demonstrated that three occur more commonly
in ICP
patients than controls. We subsequently demonstrated functional defects
for
three variants. This study showed for the first time that functional
variants in
FXR are associated with human disease and it provided pivotal pilot
data for
this proposal.
Role of reproductive hormones in ICP
Reproductive hormones also have important roles in the pathogenesis of
ICP. The
disease starts usually in the last trimester of pregnancy, when hormone
concentrations are high, and resolves after delivery2, 3.
Twin pregnancies
display both a higher incidence of ICP and more pronounced rises in
hormone
levels. Additionally, ICP patients often present with cholestasis
outside
pregnancy when taking oral contraceptives. The molecular mechanisms
through
which reproductive hormones influence bile homeostasis are currently
poorly
understood. Further studies to elucidate the role of reproductive
hormones in
bile homeostasis will be essential to unravel the pathogenesis of ICP.
Such
studies will also have a general impact on our understanding of the
molecular
mechanisms of bile formation and may therefore improve clinical
management of
both hereditary and acquired forms of cholestasis.
In January 2007 I started my own group at the University Medical Center Utrecht, The Netherlands, investigating the role of reproductive hormones in bile homeostasis. We collaborate with Catherine Williamson's group.
Reference list
1. Chiang JY. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev 2002;23:443-463.
2. Kreek MJ. Female sex steroids and cholestasis. Semin Liver Dis 1987;7:8-23.
3. Reyes H, Sjovall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med 2000;32:94-106.
The Salamanca group, Spain
By Jose Marín
For the last 10 years the Group of Research on Experimental
Hepatology and Drug Targeting (HEVEFARM) at the University of
Salamanca, Spain
has been interested in the study of the causes and disease progression
of
obstetric cholestasis. Particular attention has been devoted to the
investigation of the consequences of bile acid accumulation in the
mother on 1)
The liver of the developing foetus and 2) The structure and function of
the
placenta. The group is also interested in evaluating the effect of
several
drugs, such as ursodeoxycholic acid, on the foetus and placenta of
these
pregnancies.
Recently,
the group has directed studies toward the investigation of treating
women with
OC using antioxidant drugs and food to enhance the protection of the
foetus and
the placenta against the oxidative stress. Oxidative stress is caused
by the
over-production of reactive oxygen-related molecules; so called
free-radicals
which arecaused by the accumulation of bile acids in the maternal
blood. Because
of the great interest in investigating this disease, and in order to
improve the
available therapy to improve the condition of these pregnant women and
reduce
risk to the foetus, several collaborative studies are being conducted.
These
form part of a joint effort with research groups from several European
countries, in particular with that of Dr. Catherine Williamson at
Imperial
College, in London.
More information on the research group, staff, activities, and a complete list of publications can be found at at the HEVEFARM Web site: (http://hepatitis.dep.usal.es/jjgmarin/HOME.html).
How you can help
There are different ways in which you can help with the research, depending on how involved you feel that you would like to be. You do not have to be pregnant to take part in the study. Please do not feel obliged to take part, but if you would like to please contact Jenny Chambers (JennyChambersoc@aol.com).
