Dr Catherine Williamson 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.
The London group
For the past 10 years, a team in London, based at Imperial College and led by Dr 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.
You can use the following links to find out more about what each member of the team is currently working on:
Dr Catherine Williamson Post-Doctoral Researchers:
PhD Students:
Dr Peter Dixon
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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.
Intrahepatic cholestasis of pregnancy (ICP)
Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease
during pregnancy. It presents with pruritus and liver impairment, and is often
complicated by fetal distress, spontaneous prematurity and unexplained
intrauterine death1. In Europe, the incidence is approximately 150 per 10,000
pregnancies2, 3. The disease has serious implications for the subsequent health
of affected women as they are at risk of developing severe liver and biliary
diseases4.
About me
I am a Dutch scientist working 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 processes5. 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 delivery6, 7. 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 contraceptives1. 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.
From January 2007 onwards, I will be starting my own group at the University Medical Center Utrecht, The Netherlands, investigating the role of reproductive hormones in bile homeostasis. We will collaborate with Catherine Williamson´s group.
Reference List
1. Williamson C, Hems LM, Goulis DG, Walker I, Chambers J, Donaldson O, Swiet M, Johnston DG. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG 2004;111:676-681.
2. Abedin P, Weaver JB, Egginton E. Intrahepatic cholestasis of pregnancy: prevalence and ethnic distribution. Ethn Health 1999;4:35-37.
3. Heinonen S, Kirkinen P. Pregnancy outcome with intrahepatic cholestasis. Obstet Gynecol 1999;94:189-193.
4. Ropponen A, Sund R, Riikonen S, Ylikorkala O, Aittomaki K. Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study. Hepatology 2006;43:723-728.
5. Chiang JY. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev 2002;23:443-463.
6. Kreek MJ. Female sex steroids and cholestasis. Semin Liver Dis 1987;7:8-23.
7. Reyes H, Sjovall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med 2000;32:94-106.
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Dr Shadi Abu-
Hayyeh
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Dr Julia
Gorelik
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Dr Anita
Banerjee
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Victoria
Geenes
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Alexandra
Milona
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Bryn Owen
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Hamimah Sheikh Abdul
Khadir
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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 pblications can be found at at the HEVEFARM Web site: (http://hepatitis.dep.usal.es/jjgmarin/HOME.html).
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).
There is also the opportunity to contribute to the production of an OC training DVD. Click here for more information.
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