Research into ICP is continuing in various locations. This page describes some of this research.
Jenny Chambers, who works with the London group.
The Maternal and Fetal Disease Research group in London is headed by:
Professor Catherine Williamson
Professor Catherine Williamson is Professor of Women’s Health at King’s College London and is head of a research group that has a major focus on the causes, consequences and treatment of intrahepatic cholestasis of pregnancy (ICP), the commonest liver disease specific to pregnancy. She first became interested in ICP when she treated several women with severe disease at Queen Charlotte’s Hospital. She then applied for a Wellcome Trust fellowship to study the disease. When this was awarded a current programme of research started. She has worked closely with Jenny Chambers from that time. The research group has become larger over the years, and now the research focus has broadened to include studies of the causes and treatment of several metabolic/endocrine diseases of pregnancy. However, the group continues to work on ICP.
Professor Williamson’s research group has identified inherited factors that contribute to the development of ICP. This explains why the mothers, sisters and daughters of women with ICP are more likely to have the condition. In brief, there are genetic changes in affected women that influence the way their bodies make and remove bile acids. Bile acids are substances that help the body digest fats, and they also influence some aspects of metabolism, e.g. cholesterol levels. These genetic changes result in a tendency to have high bile acid levels. The research group has shown that high levels of pregnancy hormones can cause the bile acid levels in the blood to increase further in predisposed women, and ongoing aspects of the work on hormones are funded by the Wellcome Trust. There is still a lot more to learn about genetic causes of ICP, and the group is delighted that ICP has been selected as one of the diseases to be studies as part of the BRIDGE Consortium. This is a large project, funded by the National Institute of Health Research and Genomics England, that will provide support to sequence all of the DNA of over 250 women with severe, early onset ICP to help discover new genes that may cause the disease.
Professor Williamson’s research group has shown that high bile acid levels are likely to play a role in ICP-associated stillbirth, preterm labour and fetal hypoxia in a large study of all affected women in the UK over a one-year period. The group has also demonstrated that exposure to bile acids whilst in the womb predisposes the offspring to obesity and high cholesterol in later life. In collaboration with clinical scientists in the UK and internationally she is currently studying therapies that will protect against poor pregnancy outcome and longer term complications for the children of pregnancies affected by ICP. She is also studying the relationship between cholestasis and gestational diabetes. One new study that is due to start in 2015 is a trial of the drug ursodeoxycholic acid (UDCA) compared to placebo (a dummy drug) to see if UDCA treatment protects against poor pregnancy outcomes in ICP.
Professor Williamson’s group also uses the UKOSS system to perform national cohort studies of endocrine tumours in pregnancy and she is an author of the Confidential Enquiry into Maternal Deaths. She has been awarded more than £1 million in research funds from the Wellcome Trust to study metabolic diseases of pregnancy, and is also funded by Wellbeing of Women, SPARKS charity, The European Union and the Genesis Research Trust.
Other members of the group are:
Dr Peter Dixon
Peter Dixon is a post-doctoral research scientist who specializes in genetic and metabolomic studies. He has spent a considerable part of his career unravelling the maternal genetic component of ICP susceptibility as part of the Maternal and Fetal Disease Group.
Jenny Chambers is the Clinical Trials Coordinator administering all of the group’s studies. She helps design and implement the studies and both oversees and carries out recruitment to them. She provides data from the studies to the researchers whenever needed. As founder of ICP Support, Jenny is able to liaise with the charity both to recruit participants for research and to disseminate the results of that research.
Dr Caroline Ovadia
Caroline Ovadia is a Chadburn Clinical Lecturer and Obstetrician whose PhD was supported by ICP Support. Her interests are in medical conditions affecting women in pregnancy and the management of ‘high-risk’ pregnancies. She is researching how the gut microbes affect the body’s handling of bile acids and lipids in ICP, and how this affects the children of these pregnancies. Caroline has also led an international collaboration to determine how ICP affects the outcome of these pregnancies.
Dr Saraid MacIlvride
Saraid McIlvride is the research technician for the group. She is interested in metabolic adaptations that occur during normal and pathological pregnancy.
Alice Mitchell is a postdoctoral researcher in the group. She investigates how progesterone sulfates, which are increased in ICP, affect how the body processes hormone signals from the gut, and how this impacts whole body metabolism.
Here is what Professor Williamson has to say about the work they are conducting.
Our group has studied different aspects of intrahepatic cholestasis of pregnancy over the past 15 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 variations 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 ICP 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. We are delighted to be part of the BRIDGE Consortium (funded by the National Institute of Health Research), a collaborative group that will use a state-of-the-art whole genome sequencing approach to study genetic factors that cause women with severe ICP to develop the condition.
In addition to studying the genetic causes of ICP 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 and progesterone and their metabolites influence the way the liver controls bile acid levels in the blood. We and others have shown that breakdown products of progesterone (progesterone sulphates) rise over 100-fold in pregnancy, and that they rise 4–5 times more in cholestasis. At these high levels the progesterone sulphates interfere with the normal way that the liver removes bile salts from the body, and it is likely that this results in cholestasis in susceptible women. Several groups, including ours, have also shown that high levels of oestrogen can also affect the way that the body maintains normal levels of bile salts 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 (in collaboration with Professor Julia Gorelik, Imperial College London). We are studying how different drugs may prevent bile acid-induced damage to fetal tissues.
We recently performed a UK-wide study of severe ICP (defined by the mother having bile acid levels >40 micromol/L in the blood) and showed that this group of women have an increased risk of spontaneous preterm labour, meconium-stained amniotic fluid and stillbirth. Future work will aim to clarify what level of bile acids is not associated with increased risk and also whether drug treatment can prevent this (see the section about the PITCHES study below).
We have recently reported a new study about the longer term impact of cholestasis on the children of affected women. Using a variety of techniques our experiments suggest that exposure to high levels of bile acids in the womb may cause babies from ICP pregnancies to have an increased risk of high BMI and fatty liver when they reach adulthood. This is still preliminary work, and ongoing studies are aiming to find out whether this is a true association, and whether treatment of ICP can prevent this happening.
Work performed by several groups has shown that the drug ursodeoxycholic acid (UDCA) improves the symptoms and liver test abnormalities of women with ICP. 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. We initially collaborated on a study which was coordinated by Nottingham University and has several collaborating hospitals, including St Thomas’s Hospital (King’s College London), Queen Charlotte’s Hospital and St Mary’s Hospital from Imperial College London, Sunderland Hospital, Kings Mill, Mansfield and Heartlands/Good Hope Hospital, Birmingham. This showed that UDCA treatment improves itch and some liver function tests. However, it was a relatively small trial and there were not enough participants for us to be able to establish whether UDCA treatment can reduce the rate of adverse pregnancy outcome. Therefore we are now planning a much bigger study to address this question. This will be a prospective, double blind, placebo-controlled trial that involved 30 hospitals across the UK. This will be coordinated by Dr Chappell at St Thomas’s Hospital. The principal recruiting centres are St Thomas’s, Queen Charlotte’s, St Mary’s and Nottingham City Hospitals. The study is funded by the MRC and NIHR and samples will be collected from women cared for at these hospitals so Professor Williamson’s group can do research with the aim of understanding the cause of complications of ICP for affected women and their babies.
Other research projects within the group include studies of:
- How sleep and eating patterns affect metabolism in pregnancy
- The relationship between ICP and gestational diabetes mellitus
- The role of adipose tissue stores on bile acid and lipid metabolism in ICP, GDM and uncomplicated pregnancy
- Ways that microbes in the gut can influence susceptibility to ICP and GDM
- New drugs that improve ICP in women that don’t respond sufficiently to UDCA
Our work has used a considerable number of samples from women who have had ICP 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 ICP and their babies in the future.
By Dr Saskia van Mil
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.
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.
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.
By Jose Marín
Since 1997, 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 intrahepatic cholestasis of pregnancy. 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 ICP 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 are caused 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 via the HEVEFARM Web site: (http://www.usal.es/webusal/en/node/342).