Causes of Intrahepatic Cholestasis of Pregnancy
Causes of Intrahepatic Cholestasis of Pregnancy


Intrahepatic Cholestasis of Pregnancy is usually caused by a genetic disorder. The elevated levels of hormones in pregnancy (estrogen and progesterone) affect the transport of bile through the liver leading to elevated levels. Environmental factors play a role but are poorly understood.

Intrahepatic Cholestasis of Pregnancy (ICP) is a genetic disorder. People who develop ICP have a genetic predisposition, but not everyone with the predisposition will develop ICP. There are other factors, some known and some unknown, which influence whether or not ICP occurs in any given pregnancy. This can make it difficult to predict who will develop the disorder.


Intrahepatic Cholestasis of Pregnancy is not a single disorder, but rather a family of related liver disorders of pregnancy. There are many genetic variants that have been identified, and many others which have not. These genetic variants affect a number of different genes which impact several different functions of the liver, but they are all similar because they lead to increased bile acids in the patient’s blood. Because, in part, of the genetic diversity of ICP, it varies widely in its presentation from one person to another.

We know that inheriting a single copy of a gene for Intrahepatic Cholestasis of Pregnancy is enough to put us at risk for developing ICP1. This can be confusing for many people, because there may be no family history of ICP, but it is still due to a genetic predisposition. ICP can be inherited from either parent, and not everyone who inherits a gene will develop ICP during their pregnancies, meaning both male and female relatives may carry the gene but display no symptoms. However, due to the genetic nature of ICP, relatives of ICP patients are at higher risk for developing ICP in their own pregnancies. In some cases, patients may develop elevated bile acids during pregnancy due to an underlying liver disease or disorder. While this isn’t “true” ICP, it should still be treated the same.


Genetics Cholestasis of Pregnancy

A helpful diagram to understand the Genetics of Intrahepatic Cholestasis of Pregnancy (ICP).

Note: This image is a simplified graphic intended to demonstrate the patterns of inheritance that ICP appears to follow and not to demonstrate the actual inheritance of the genes which have been discovered thus far. Its purpose is to help the layperson without an advanced scientific background understand basics of genetics and not the actual genetics of known Intrahepatic Cholestasis of Pregnancy genes. Actual inheritance is more complex.

Hormonal Influences

While the gene for Intrahepatic Cholestasis of Pregnancy is always present in affected individuals, it doesn’t become apparent until the addition of increased hormones, specifically estrogen and progesterone. Both hormones have been found to have a role in the development of ICP2,3. As pregnancy progresses, estrogen and progesterone levels increase, and the hormones interfere with the liver’s ability to move bile out of the cells normally. Since hormone levels are higher later in pregnancy, ICP most commonly develops in the third trimester, though there are documented cases as early as five weeks gestation4.

Anything that leads to higher levels of estrogen and progesterone during pregnancy also increases the risk of developing Intrahepatic Cholestasis of Pregnancy. Progesterone therapy5, in vitro fertilization6, and multiple pregnancies (twins, triplets, etc.)7 are all risk factors.

Environmental Factors

We know that environmental factors also play a role, because not everyone who develops Intrahepatic Cholestasis of Pregnancy in a pregnancy will go on to have it in their next pregnancy. Likewise, people sometimes have a normal pregnancy followed by an ICP pregnancy. Unfortunately, little is known about these environmental factors. Isolated studies have linked ICP with pregnancy during winter months and selenium deficiency8, although there is no evidence to suggest an improved diet reduces the risk of ICP. However, some people feel anecdotally that diet changes have improved their ICP symptoms.

Read about the Risks associated with ICP

  1. Geenes V, Williamson C: Intrahepatic Cholestasis of pregnancy. World J Gastro 2009;15:2049-2066
  2. Stieger B, et al: Drug- and Estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 2000 Feb;118(2):422-30.
  3. Abu-Hayyeh S, Ovadia C, Lieu T, et al: Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology, 2015;doi:10.1002/hep.28265.
  4. Wongjarupong N, et al: Never Too Soon: An Unusual Case of Intrahepatic Cholestasis of Pregnancy at Five Weeks Gestation. Cureus. 2020 Sep; 12(9): e10540.
  5. Bacq Y, Sapey T, Brechot MC, et al: Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology 1997;26:358-364
  6. Pacella G, Salsi G, Archangeli T, et al: The impact of assisted reproductive technology and chorionicity in twin pregnancies complicated by obstetric cholestasis. J Matern Fetal Neonatal Med, 2015; doi:10.3109/14767058.2015.1051954
  7. Gonzalez MC, Reyes J, Arrese M, et al: Intrahepatic cholestasis of preganancy in twin pregnancies. J Hepatology 1989;9:84-90
  8. Reyes H, Maez ME, Gonzalez MC, et al: Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals, in Chile. J Hepatology 2000;32:542-549