Etiology
The condition likely occurs because of the interplay of reproductive hormones with environmental factors in genetically susceptible individuals. ICP occurs more commonly in first-degree relatives, and the most common mutations revealed by genetic studies demonstrate alterations in components of the bile secretory pathways.[31] Examples include mutations in the bile salt export pump (BSEP [ABCB11]), multidrug resistant protein 3 (MDR3 [ABCB4]), and familial intrahepatic cholestasis 1 (FIC1 [ATP8B1]); polymorphisms have also been identified in several other anion transporters, a tight junction protein (TJP2), and the nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR).[32][33][34][35][36][37]
Evidence for the role of reproductive hormones is as follows: the disease onset occurs most frequently in the third trimester, when circulating reproductive hormones are at their highest, and women with ICP may experience itch and hepatic impairment with the use of hormonal contraceptive treatment; rates of ICP are also higher in women receiving progesterone supplementation for the prevention of preterm birth.[38][39][40][41] 17-beta-estradiol can impair BSEP expression, glucuronidated 17-beta-estradiol enhances the endocytosis of BSEP and MDR3, and the sulfated metabolites of progesterone impair bile acid uptake and efflux by the hepatocyte, and antagonize FXR.[42][43][44][45][46] By signaling via estrogen receptor alpha, 17-beta-estradiol can impair the induction of BSEP expression by bile acid-liganded FXR in a mouse model and human cell line.[42][47] Genome-wide association studies demonstrate that common variation in several genes can influence susceptibility to ICP, including in genes related to gallstone disease. Additional causative mutations were also identified in genes encoding alpha-1-antitrypsin, glucokinase regulatory protein, hepatic nuclear factor 4 alpha, and hexokinase domain containing 1, and a number involved in cholesterol uptake and metabolism (GAPDHS, ENPP7, SHROOM3) and bile acid metabolism (CYP7A1, SULT2A1).[48][49] ICP is more common in multifetal pregnancies and in women who have conceived with assisted reproduction.[50][51]
The environmental influence is demonstrated by observations of higher disease incidence in winter months (suggesting the influence of vitamin D), increased rates of vitamin D deficiency in ICP, and reports of associations with selenium deficiency.[52][53]
Pathophysiology
There is limited evidence that the pathophysiology and severity of ICP-associated pruritus is related to bile acid concentrations.[6] The enzyme autotaxin is more active in women with ICP, and its product, lysophosphatidic acid, is a potent pruritogen.[54] Similarly, levels of the sulfated progesterone metabolite, PM3S, correlate with itch severity; it can signal through TGR5 on nerve cells to stimulate itch.[55]
The impaired glucose tolerance and dyslipidemia of ICP are likely to result from altered hormonal activities of bile acids in affected women.[56][57][58] Glucagon-like peptide 1 (GLP1) is responsible for 70% of glucose-mediated insulin release, and levels are lower in women with cholestatic pregnancy.[57]
Under normal circumstances, there is a gradient of bile acid concentrations across the placenta such that bile acids in the fetal compartment are at higher concentrations and so pass back toward the mother, but in ICP this gradient is reversed, and maternal bile acids are transported through the placenta to the fetus.[59] Thus, fetal serum bile acid concentrations are higher in ICP and are thought to be responsible for the majority of fetal complications.[2] Infusion of bile acids into the amnion increases preterm birth in lambs, whereas uterine oxytocin-dependent myometrial activity increases in the presence of cholic acid (the bile acid most increased in ICP).[60][61] Similar increases in the smooth muscle of the intestine secondary to bile acids may explain the increased passage of meconium in utero.[62] Increased concentrations of bile acids in the lungs of neonates from ICP pregnancies may explain the increase in respiratory morbidity, as bile acid signaling in macrophages induces the production of phospholipase A2, which breaks down surfactant.[63][64]
Two main theories exist for the pathophysiology of stillbirth in ICP: a cardiac event in the fetus or placental impairment. Stillborn babies of cholestatic pregnancies are usually normally grown, without evidence of chronic placental insufficiency; babies often have normal fetal monitoring very close to the stillbirth, with no predictive ability to suggest fetal distress.[65][66][67] Thus, a sudden catastrophic event is thought to occur, such as cardiac arrhythmia or placental vasoconstriction. Fetal cardiomyocyte function is impaired in vitro by the bile acid taurocholic acid. In addition, fetal echocardiographic differences have been seen in cholestatic pregnancies compared with uncomplicated pregnancies, with prolongation of the fetal PR interval reported.[68][69][70] Cardiac troponin levels in umbilical cord blood (a marker of cardiac damage) were higher in a small group of women with ICP compared with uncomplicated pregnancies.[71] Additionally, umbilical cord N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of ventricular dysfunction, and fetal PR interval and heart rate variability were increased in pregnant women with ICP compared with uncomplicated pregnancies.[72] Similarly, taurocholic acid impaired placental arterial vascular pressure elevation in an ex vivo model, while inducing placental vasoconstriction.[73]
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