Molecular Pathogenesis of Intrahepatic Cholestasis of Pregnancy

Abstract

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease. The maternal symptoms are characterized by skin pruritus and elevated bile acids, causing several adverse outcomes for fetuses, including an increased risk of preterm birth, meconium-stained amniotic fluid, neonatal depression, respiratory distress syndrome, and stillbirth. Genetic, hormonal, immunological, and environmental factors contribute to the pathogenesis of ICP, and the estrogen-bile acid axis is thought to play a dominant role. The advances in the past 10 years uncover more details of this axis. Moreover, dysregulation of extracellular matrix and oxygen supply, organelle dysfunction, and epigenetic changes are also found to cause ICP, illuminating more potential drug targets for interfering with. Here, we summarize the molecular pathogenesis of ICP with an emphasis on the advancement in the past 10 years, aiming to give an updated full view of this field.

Identification of two novel pathogenic variants of the NR1H4 gene in intrahepatic cholestasis of pregnancy patients

“…Therefore, it is also likely reasonable that there is no significant difference in TBA levels between wild-type and NR1H4 mutations even though the mutation group tended to be associated with higher TBA levels when considering the allele frequency and size effect. Except for the ICP caused by the NR1H4 mutations, we speculated that other gene mutations (such as ANO8 , ATP-binding cassette transporter family, bile acid receptors) [ 20 , 35 , 43 ], epigenetic regulators (microRNAs, DNA methylation and histone modification) [ 44 – 46 ], oestrogen and progesterone sulfate metabolites [ 10 , 47 ], hypoxia [ 48 ] and the immune system [ 49 ], among other factors [ 50 ], may be responsible for the remaining ICP patients in this study.…”

Pruritus in Pregnancy

“…A striking geographic variation is noted, with an incidence as high as 28% especially in patients with overt Araucanian Indian descent [ 86 ]. Mutations of ABCB4 ( MDR3 ) involved in the biliary secretion of phospholipids have been studied in ICP and may play an important role, at least in some patients [ 87 ]. Diseases associated with ICP include gallstones [ 88 , 89 ], hepatitis C infection [ 90 , 91 ], preeclampsia, and gestational diabetes [ 92 – 94 ].…”

“…Potential etiopathogenetic factors include genetic (altered expression of hepatobiliary transport proteins), hormonal (especially estrogen levels), and environmental factors such as seasonal variability and diet [ 87 , 98 ]. Recent studies have explored the role of alterations in gut microbiota and long-term therapy with vaginal progesterone preparations as potential risk factors for ICP [ 99 , 100 ].…”

State of the Art in Hepatic Dysfunction in Pregnancy

“…A series of changes in the genes BSEP/ABCB11, MDR3/ABCB4, GABRA2, and ATP8B1/FIC1 were observed in patients with ICP, which is associated with lesions of biliary ducts and hepatocyte membrane. Furthermore, severe ICP forms show genetic variants of MDR3 and BVB [73][74][75].…”

“…ICP was reported more frequently in women with ovarian hyperstimulation, multiple pregnancies, or those previously treated with oral contraceptives. The disease more frequently develops in women with underlying liver diseases such as hepatitis C or nonalcoholic cirrhosis, but in most cases, there is no personal history of liver dysfunction [71,73].…”