July 19th 2012
Intrahepatic Cholestasis of Pregnancy
The time before having a baby is definitely an itchy, nerve-racking experience. I wouldn’t know this, being a guy and a college undergraduate, but I can infer. Occasionally, however, the itchiness isn’t just anticipation but can actually be caused by something called intrahepatic cholestasis of pregnancy. This condition sounds daunting, but fortunately recent research has provided successful intervention.
What is Cholestasis?
Cholestasis is a general condition, common among many diseases associated with the liver, which happens when something goes wrong in bile production. Normally when a person ingests fats, the body uses bile as a catalyst in fat digestion and absorption. Cholestasis is caused by a disruption in the synthesis of bile in the liver that produces unwanted compounds in the blood circulation1. Intrahepatic cholestasis of pregnancy (ICP) is a milder, subtype of cholestasis, the most common symptom of which is pruritus, or itch.
What exactly goes wrong?
We have known for a long time that the itch associated with cholestasis is caused by a byproduct of bile synthesis. The culprit blamed for the condition has been the improper transport of the components of bile into the liver. Previously it was thought that compounds, which activated a type of receptor called a mu-opioid receptor, were capable of eliciting itch. Some of the support for this claim came from test trials that prescribed to patients certain drugs that blocked the mu-opioid receptors and inhibited itch2. Unfortunately, these drugs often produce undesirable effects similar to opium or morphine withdrawal. Recent studies have shown that elevated levels of compounds that act on mu receptors are not correlated with itch, although they are correlated with cholestasis2. Thus the search continued for what was causing itch in pregnant women with cholestasis.
What’s estrogen got to do with it?
Cholestasis associated with pregnancy usually surfaces in the third trimester, a time when estrogen levels are increasing in anticipation of birth. The hormone estrogen has been directly linked to disruption of bile production in the liver by acting on the channels that allow bile salts to be transported into and out of the liver3. It has also been linked to cholestasis through indirect action such as altering the membranes of the cells that produce bile.
This figure shows some of the receptors (circles) involved in
transporting bile metabolites into and out of hepatic cells8.
LPA and ATX are the culprits
The breakthrough came in 2011, when researchers were able to identify a specific molecule that was present in much higher amounts in itchy cholestatic patients than in those who did not experience itch. This compound is called lysophosphatidic acid (LPA), and it is activated by an enzyme called autotaxin (ATX)4,5. Both of these compounds appear in conjunction with an increase in estrogen production in genetically vulnerable individuals, described in more detail below. LPA acts on several different receptors that signal to the brain a message that is interpreted as itchiness. The LPA/ ATX connection was an extremely novel idea—no one had ever connected either of these compounds with pruritus before. New research is now targeting both LPA and ATX as potential places for therapeutic intervention.
Intrahepatic cholestasis of pregnancy presents a number of interesting features and puzzles. The disease occurs in about 1-2% of pregnant women, but in northern latitudes the rate of prevalence increases significantly during the colder, winter months. Among pregnant women with this condition, itch is the most common symptom, but the itch isn’t everywhere—hands and feet itch the most. The itch tends to get worse at nighttime, as if the disease runs its course in accordance with a circadian rhythm. Possibly fluctuations in symptoms of itch could be caused variations in estrogen release. Women who have twins or triplets produce much more estrogen than do mothers of singletons and as many as 20% of mothers of twins or triplets are cholestatic during their pregnancy.
Why are some women more at risk than others?
Genetics are also clearly involved in a woman’s susceptibility to cholestasis. Genetic variations in many of the protein receptors and channels involved in bile production and secretion are seen as plausible factors in developing the condition. A good example is the bile acid sensor FXR, which helps to maintain low levels of bile acids in the liver and digestive tract7. Mutations in the gene that codes for FXR have been shown to cause reduced protein activity and probably an increased likelihood of ICP. Interestingly, most women who experience ICP have one normal copy of the gene that codes for FXR and one mutated variant copy. This is why they are completely healthy normally and only show signs of cholestasis during pregnancy when estrogen levels rise.
ICP is a transient condition in the mother that usually subsides within days after delivery, but fetal outcome may be affected. Premature births, as well as increased bile salt acids in the fetus, are linked to cholestatic mothers. Current therapeutic intervention involves administration of the bile acid UDCA, which has been shown to improve liver enzyme function, reduce pruritus, and prolong pregnancy with no adverse side effects3. Other drugs being used to treat patients with malignancies through blocking the action of ATX and LDA are promising future options for ICP treatment5.
1. Mela, M., Mancuso, A., et al. (2003). “Review article: pruritus in cholestatic and other liver diseases.” Alimentary pharmacology & therapeutics 17(7): 857-870.
2. Heathcote, J. (1996). “The pruritus of cholestasis is relieved by an opiate antagonist: is this pruritus a centrally mediated phenomenon?” Hepatology 23(5): 1280-1282.
3. Arrese, M., Macias, R. I., et al. (2008). “Molecular pathogenesis of intrahepatic cholestasis of pregnancy.” Expert reviews in molecular medicine 10: e9.
4. Oude Elferink, R. P., Kremer, A. E., et al. (2011). “Mediators of pruritus during cholestasis.” Current opinion in gastroenterology 27(3): 289-293.
5. Kremer, A. E., Martens, J. J., et al. (2010). “Lysophosphatidic acid is a potential mediator of cholestatic pruritus.” Gastroenterology 139(3): 1008-1018, 1018 e1001.
6. Greenes, Victoria, Williamson, Catherine. World J Gastroenterol 2009 May 7; 15(17): 2049-2066.
7. Van Mil, S. W., Milona, A., et al. (2007). “Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy.” Gastroenterology 133(2): 507-516.
8. Arrese, M., Ananthananarayanan, M., Suchy, F.J. “Hepatobiliary transport: molecular mechanisms of development and cholestasis.” Pediatr Res1998;44:141–7.