Intra-Hepatic Cholestasis of Pregnancy
1st Year MBBS, Islamabad Medical and Dental College
Intrahepatic cholestasis of pregnancy is a pregnancy-speciﬁc liver disease which compromises symptoms like skin pruritus (itching) and elevated level of bile acids. Symptoms in the pregnant woman appear in the second or third trimester but in some cases, they emerge in the ﬁrst trimester and goes back to normal after delivery. This disease arise in around 0.5-2% pregnancies.1
One of the several causes of ICPincludes genetic mutation of the hepatobiliary transport protein-multidrug resistance protein 3 (MDR3). These transport proteins are involved in the secretion of phospholipids. This kind of mutation is appreciated in almost 16% of the ICPpatients that have bile acid level higher than 40 μmol/L. MDR3 disorder, however, can also be seen in people having low phospholipid level by birth or even due to induced cholestasis. In some cases, intrahepatic cholestasis can also be caused by change in BSEP (bile salt export pump) gene in which amino acid on 444 position is substituted. In addition to the mutations in MDR3 and BSEP genes, rare mutations in the FIC1 gene (ATP8B1) which is present inside the bile duct membrane and the FXR gene (NR1H4) were also detected in the patients in Caucasus and steroid hormones or their metabolites are said to be the cause of such mutations.2 Another major cause is the increase in bile acid level which accumulate in hepatocytes and damage the cell membranes which in turn releases aminotransferases, bilirubin, γ- glutamyl transpeptidases, and alkaline phosphatase into the blood serum. In ICP patients, the bile acid ﬂow is reversed from mother to fetus which enhances the levels of bile acids in the fetus. In Laatikainen, a higher concentration of BAs (bile acids) was found in the umbilical cord blood of fetuses from ICP (approximately 5.6 μg/mL) as compared to fetus from normal pregnancy (1.8 μg/mL). The stimulus of this reversal is said to be the structural and functional change in placenta. In an advanced pregnancy, when the mother's liver is exposed to high levels of sex hormones, an increase in the level of BAs in both the mother and the fetus along with abnormal functioning of the placenta will make it impossible to synthesize water-soluble BAs, that will causes disturbances in BAtransport across the placenta and ICPdevelopment.The accumulation of BAs in the maternal and fetal liver in ICP may lead to oxidative stress and hepatocyte apoptosis, which may affect time period of the pregnancy. The sex hormones are metabolized in the liver. Anumber of studies conﬁrmed the effects of gestational hormones on the metabolism of bile acids; however, many of these studies were conducted in animal (mainly murine) models for ethical reasons. Glucuronates, estrogens, and progesterone disturb the function of hepatobiliary transport proteins that are involved in the excretion of bile acids into the hepatic bile ducts. It changes the composition of bile, and the ratio of hydrophilic and hydrophobic bile acids is also disturbed. This results in the impairment of water-soluble bile acids being transported across the placenta and excreted by maternal kidneys. Balance of BAs in maternal and fetal blood plays an important role in ICP. 2
Effect on the fetus
Intrahepatic cholestasis may gravely threaten fetal growth and development, resulting in intrauterine fetal distress and death, premature delivery, neonatal hypoxia-ischemia (brain damage) and asphyxia (deﬁciency of oxygen). Long-term high bile acid level, especially high CG (chorionic gonadotropin) level will cause contraction in vessels on the surface of placental villi and decreased ﬂow of blood and oxygen level and lesser exchange of nutrients from the mother. This will ﬁnally terminate in intrauterine fetal distress and affect growth and development of the fetus3
Treatment of ICP can be accomplished in several ways to minimize the harmful effects on the fetus. Non-pharmacological treatment (without the involvement of drugs) includes satisfactory bed time routine which leads to improvement of hepatic blood ﬂow, monitoring the fetus by using biophysical methods like ultrasound examination, monitoring the fetal movements by the pregnant woman, and monitoring of concentrations of hepatic functional tests. Weekly tests to note the bile acid levels are also suggested according to which time of delivery is recommended. For example:
- at the concentration of 40 μmol/L total bile acids, childbirth is recommended between 37 and 38 weeks of pregnancy.
- at the concentration of 40–99 μmol/L total bile acids, childbirth is recommended between 36 and 37 weeks of pregnancy.
- Dixon PH, Levine AP, Cebola I, Chan MM, Amin AS, Aich A, Mozere M, Maude H, Mitchell AL, Zhang J. GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements. Nature communications. 2022 Aug 17;13(1):4840.
- Piechota J, Jelski W. Intrahepatic cholestasis in pregnancy: review of the literature. Journal of Clinical Medicine. 2020 May 6;9(5):1361.
- Majsterek M, Wierzchowska-Opoka M, Makosz I, Kreczynska L, Kimber-Trojnar Ż, Leszczynska-Gorzelak B. Bile acids in intrahepatic cholestasis of pregnancy. diagnostics. 2022 nov;12(11):2746.
- Wang L, Lu Z, Zhou X, Ding Y, Guan L. Effects of intrahepatic cholestasis of pregnancy on hepatic function, changes of inﬂammatory cytokines and fetal outcomes. Experimental and therapeutic medicine. 2019 Apr 1;17(4):2979-84.
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