Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta

Department of Biochemistry and Molecular Biology, University of Salamanca, Spain.
Journal of Hepatology (Impact Factor: 11.34). 06/1998; 28(5):829-39. DOI: 10.1016/S0168-8278(98)80234-1
Source: PubMed


The existence of impairment in bile acid transport across the placenta during intrahepatic cholestasis of pregnancy and the effect of ursodeoxycholic acid treatment (1 g/day) were investigated.
Kinetic parameters were calculated from experiments carried out on membrane vesicles obtained from basal (TPMb, fetal-facing) and apical (TPMa, maternal-facing) trophoblast plasma membranes. Bile acid uptake was measured using varying concentrations of [14C]-glycocholate and a rapid filtration technique.
The maximal velocity of transport (Vmax), the apparent affinity constant (Kt) and the efficiency (Ef) of transport (Vmax/Kt) of the anion:bile acid exchanger located at the TPMb were reduced in intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid induced a reversal of Vmax, Kt and Ef to normal values. Owing to the 3-fold increase in Vmax, with no change in Kt, intrahepatic cholestasis of pregnancy induced an enhancement in Ef of ATP-independent bile acid transport across TPMa. Both Vmax and Ef were restored to normal values by ursodeoxycholic acid. Finally, in ATP-dependent bile acid transport across TPMa, a reduction in the Ef due to an increase in Vmax together with a more pronounced increase in Kt was found. This impairment was also reversed by ursodeoxycholic acid.
These results suggest that placenta bile acid transport systems are impaired in intrahepatic cholestasis of pregnancy. Moreover, together with the confirmed beneficial effect for intrahepatic cholestasis of pregnancy patients, such as the relief of pruritus and the improvement in biochemical markers of cholestasis, ursodeoxycholic acid treatment restores the ability of the placenta to carry out vectorial bile acid transfer.

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    • "The best biomarker for diagnosis and follow-up of ICP is up to knowing percentage levels of bile acids (taurocholic and glycocholic acids) over 40% with TBA ≥14 mmol/L. The level of bile acid is found to be associated with fetal complications [1, 4]. Howard and Murphy found that fetal serum TBA was higher than that of the maternal level during late stage of normal pregnancy [4]. "
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    ABSTRACT: Objective. To determine the correlation between maternal bile acid (BA) level and fetal pulmonary surfactant in rats and study the effects of BA on fetal lung in rat model of intrahepatic cholestasis of pregnancy. Methods . Forty pregnant rats were treated with (A) 5.5 mg/kg BA, (B) 1.4 mg/kg BA, and (C) 1 ml physiological saline. Levels of total bile acid (TBA), ALT, AST, TBIL, DBIL, and SP-A were determined and the lungs of fetal rats were analyzed for pathological changes. Results . Groups A and B intervened with BA showed significant higher level of TBA in both maternal and fetal serum, more mortality rate of fetal rats, more concentration of SP-A in fetal serum, and wider alveolus mesenchyme of fetal rats than the control Group C. Higher level of BA associated with increased fetal risk and lower numerical density of mitochondria in type II alveolar epithelial cells. The levels of TBA in maternal serum were found to have significant positive correlation with those in fetal serum and SP-A level but negatively with the area of alveolus and the numerical density of lamellar body. Conclusions . The TBA level in maternal serum showed significant association with lung pathological changes in fetal rats.
    International Journal of Endocrinology 03/2014; 2014(1):308274. DOI:10.1155/2014/308274 · 1.95 Impact Factor
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    • "In cases of intrauterine fetal loss, observation of fetus autopsy is consistent with death from acute intrauterine anoxia. Meconium and bile acids, especially cholic acid (CA), have been indicated to induce vasoconstriction of human placental chorionic veins in vitro (Serrano et al., 1998) as well as to cause acute umbilical vein constriction (Altshuler et al., 1989; Altshuler et al., 1992). Although bile acid mechanisms are not yet defined, it is well known their toxic action. "

    Cholestasis, 02/2012; , ISBN: 978-953-51-0043-0
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    • "A variety of other medications have been tried to alleviate maternal symptoms, but have not been shown to alter fetal prognosis. UDCA has been shown to restore the impaired bile acid transport across the throphoblast [13] and decrease the delivery of bile acids to the fetus [6] [14] [24]. Up to now, no adverse effects on the fetus of UDCA therapy has been reported. "
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    ABSTRACT: Abbreviations CTG = cardiotocography; ICP = intrahepatic cholestasis of pregnancy; UDCA = ursodeoxycholic acid Intrahepatic cholestasis of pregnancy (ICP) usually presents in the third trimester and rarely before 25 weeks' gestation [1]. It is characterized by pruritus, mild jaundice [2], fat malabsorption and raised maternal liver enzymes and bile acids. The overall prevalence of the disease is estimated at 1/1000 to 1/10000 pregnancies [3]. Scandinavia (2%) and Chile (4%) have the highest preva-lence [2, 4]. There is no uniform agreement on the criteria for diagnosing ICP. Knox and Olans [5] assert the role of elevated liver enzymes, whereas Palma et al. [6] emphasise that the most sen-sitive laboratory signs are the elevated total serum bile acids. Rioseco et al. suggest that the diagno-sis can be made clinically based on altered laboratory results and typical symptoms [7]. Intrahepatic cholestasis of pregnancy is characterized by pruritus, raised maternal liver enzymes and bile acids. It usually presents in the third trimester and rarely before 25 weeks. Ursodeoxycholic acid is the most promising therapy to alleviate symptoms and prevent fetal risk. However, its administration has been restricted for the last trimester as its embryotoxic effect is undetermined. We report here a case of an extremely rare, severe obstetric cholesta-sis with early onset treated by ursodeoxycholic acid from the 9 th week of pregnancy, the earli-est ever reported in the literature. The treatment was well tolerated. At the 32 nd week urgent caesarean section was performed due to intolerable symptoms, worsening laboratory results and signs of fetal distress. A healthy newborn was delivered. It is concluded that ursodeoxy-cholic acid in case of a severe early-onset intrahepatic cholestasis may be started in the early pregnancy to improve maternal condition and prevent fetal complications.
    03/2009; 3(1). DOI:10.1556/CEMED.3.2009.1.14
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