Touching Lives - June 2005
Investigating the 'itching disease'
However, if a blockage occurs in the liver and the bile begins to build up, it is released into the bloodstream where it can be highly toxic and damaging — especially for a developing fetus.
Obstetric cholestasis (OC) affects about 1 in 200 pregnancies in the UK. It is a serious condition, characterised by itching, that often leads to premature delivery or stillbirth late in pregnancy. High levels of bile acids are found in the bloodstreams of mothers and babies in a significant number of premature and stillbirths, suggesting that OC could be more common than has been previously recognised.
The bile flow
Obstructions to the flow of bile can be physical, such as a tumour, or can occur at a micro-level. Bile is carried on its journey by transporter proteins, and if these are genetically damaged, or mutated, the circulation within the liver can be impaired.
^There are several transporters which the body uses, and genetic mutations occur in two of them in women who have had OC.^ There are also regulator proteins which “oversee” the transporters, and sound the alarm if circulation is going wrong. Dr Catherine Williamson of the Institute of Reproductive and Developmental Biology at Imperial College London is looking at the role of a particular regulator protein called FXR, and what it does in mothers and their unborn babies.
Regulator proteins act as a kind of thermostat to the system that controls bile acids. If bile builds up in cells, these regulators detect it. To avoid the toxins damaging the cells, they expel the bile acids into bile or allow them to accumulate in the bloodstream.
If a pregnant woman has a genetic mutation that causes raised bile acids in the blood, and experiences further slowing of bile flow caused by hormones such as oestrogen circulating during pregnancy, it may trigger the malfunction in bile circulation that leads to OC.
In OC, the high levels of bile acids pass through the placenta to the fetus and put it at risk of stillbirth and prematurity. If the fetus inherits the mutation from the mother this may reduce the ability of the placenta to remove the high bile acids from the fetus.
Exciting new study
Dr Williamson and her team will be examining DNA samples from over 500 mothers. If they find genetic abnormalities in FXR they will use a technique that involves luminous material (from glow worms!) to evaluate how the faulty regulator protein affects bile circulation.
The team will go on to explore the role of FXR in the placenta to see if there is a “blockage” in the waste disposal system between fetus and mother. In the last phase of the project they will investigate the role of transporters and regulator proteins in the fetus. ^Bile acid composition is different in unborn babies, and indeed it is something of a mystery why they manufacture bile acid at all^, since they don’t eat and so don’t use a digestive system in the adult sense.
Dr Williamson hopes that the clinical outcome will be to develop a way of identifying women at risk of OC and its potential complications. At that stage doctors could evaluate whether drug treatment works, or whether mothers should opt for early delivery to pre-empt the chance of stillbirth.