Professor Catherine Williamson
Maternal & Fetal Disease Group
Group Head - Catherine Williamson (Professor in Obstetric Medicine)
Aims
- To elucidate the molecular aetiology of cholestatic diseases of pregnancy
- To investigate the interaction between the maternal and fetal genotype in diseases of pregnancy
- To establish the role of nuclear receptor signalling and reproductive hormones in lipid and bile acid homeostasis
- To understand the cause of the fetal complications of cholestasis of pregnancy
- Elucidation of the molecular aetiology of cholestatic disorders of pregnancy
Obstetric cholestasis is a liver disease of pregnancy that affects approximately one in 200 pregnancies in the UK. It causes itch and abnormal bile acid homeostasis in affected women and is associated with spontaneous prematurity, fetal distress and unexplained third trimester intrauterine death. The condition has a genetic component to its aetiology and our group and others have demonstrated mutations in hepatic canalicular transporters (MDR3/ABCB4, BSEP/ABCB11 and FIC1/ATP8B1) and in the primary bile acid receptor (farnesoid X receptor (FXR)/NR1H4) in the disorder. However mutations in these genes do not explain all causes of obstetric cholestasis and we are therefore currently investigating the role of nuclear receptor signalling and reproductive hormones in its aetiology. The group also has a large number of placental specimens and is characterising the expression of nuclear receptors and hepatic bile acid transporters in the placenta. Studies of placental bile acid transport and metabolism are being performed in parallel with the gene expression studies.
The group is also investigating the effect of administration of reproductive hormones to women who have previously had obstetric cholestasis. We are utilising NMR spectroscopy of biological samples and in vivo NMR studies of the livers of affected women to investigate mechanisms that cause cholestasis. These studies will be extended in animal models and using hepatocyte cultures. We anticipate that this will allow more detailed analysis of signalling mechanisms and pathways that are affected by abnormal bile acid homeostasis.
The group is performing clinical and laboratory studies to investigate the cause of intrauterine death in cholestatic pregnancies. Clinical studies have confirmed that the majority of fetal deaths occur at or near term. Using in vitro studies of cultured cardiomyocytes we have demonstrated that bile acids cause abnormal calcium dynamics and dysrythmias. We have also demonstrated that drugs used to treat the condition protect against the in vitro cardiomyocyte abnormalities indicating that clinical administration of these drugs may protect the fetus from the complications of obstetric cholestasis.
Recent Publications
1. Dixon PH, van Mil SWC, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz AG, Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ, Williamson C. Contribution of Variant Alleles of ABCB11 to Susceptibility to Intrahepatic Cholestasis of Pregnancy. Gut. 2009; 58(4): 537-44.
2. Sheikh Abdul Kadir SH., Ali NN, Mioulane M, Brito-Martins M, Abu-Hayyeh S, Foldes G, Moshkov AV, Williamson C, Harding SE. Gorelik J. Embryonic stem cell-derived cardiomyocytes as a model to study fetal arrhythmia related to maternal disease. J Mol Cell Med 2009 In press.
3. Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. W J Gastroenterol. 2009; 15(17):2049-66.
4. Owen BM, van Mil SWC, Boudjelal M, Mclay I, Cairns W, Elias E, White R, Williamson C, Dixon PH. Sequencing and functional assessment of hPXR (NR1I2) variants in intrahepatic cholestasis of pregnancy. Xenobiotica 2008; 38: 1289-97.
5. van Mil SWC, Milona A, Dixon PH, Mullenbach R, Geenes VL, Chambers J, Shevchuk L, Moore GE, Lammert F, Glantz AA, Mattson L, Whittaker J, Parker MG, White R, Williamson C. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 2007 Aug; 33: 507-16.
6. Albrecht C, Soumian S, Tetlow N, Patel P, Sullivan MHF, Lakasing L, Nicolaides K, Williamson C. Placental ABCA1 expression is reduced in primary antiphospholipid syndrome compared to pre-eclampsia and controls. Placenta 2007 Jul;28(7):701-8.
7. Serrano MA, Macias RIR, Briz O, Monte MJ, Williamson C, Kubitz R, Marin JJG. Expression in human trophoblast cells of genes involved in the hepatobiliary-like excretory function of the placenta. Placenta 2007 Feb-Mar;28(2-3):107-117.
8. Gorelik J, Patel P, Ng'andwe C, Diakonov I, Lab M, Korchev Y, Williamson C. Genes encoding bile acid, phospholipid and anion transporters are expressed in a human fetal cardiomyocyte culture. BJOG 2006 May; 113(5): 552-8.
9. Gorelik J, Shevchuk AI, Ali NN, Lab M, Williamson C, Harding SE, Korchev Y. Functional characterisation of embryonic stem cell-derived cardiomyocytes using a surface scanning microscope. Tissue Engineering 2006 Apr; 12(4): 657-64.
10. Mullenbach R, Bennett A, Tetlow N, Patel N, Hamilton G, Cheng F, Chambers J, Howard R, Taylor-Robinson SD, Williamson C: ATP8B1 mutations in intrahepatic cholestasis of pregnancy. Gut; 2005 Jun;54(6):829-34
