Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta.
ABSTRACT 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.
- SourceAvailable from: Valeria Tripodi
Cholestasis, 02/2012; , ISBN: 978-953-51-0043-0
- "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. "
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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  and decrease the delivery of bile acids to the fetus   . Up to now, no adverse effects on the fetus of UDCA therapy has been reported. "
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 . It is characterized by pruritus, mild jaundice , 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 . 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  assert the role of elevated liver enzymes, whereas Palma et al.  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 . 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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- "Treatment with ursodeoxycholic acid (UDCA), which has beneficial effects in several cholestatic liver diseases (Poupon and Poupon, 1995; Kowdley, 2000; Lazaridis et al., 2001), is able to mitigate pruritus and enzyme elevations in the serum of women with ICP (Palma et al., 1992; Floreani et al., 1994; Brites et al., 1998). Because UDCA was also found to have a positive effect on ICP placentas , at least as far as BA transport by trophoblast plasma membrane vesicles was concerned (Serrano et al., 1998), in the present study we intended to further characterize structural and functional aspects of the beneficial effects of UDCA on maternal hypercholanemia-induced impairment of the rat placenta-maternal liver tandem excretory pathway for fetal BAs. "
ABSTRACT: We investigated the effects of ursodeoxycholic acid (UDCA; 60 microg/day/100 g b.wt.) on the impairment induced by maternal obstructive cholestasis during pregnancy (OCP) in the rat placenta-maternal liver tandem excretory pathway. A blunted catheter was implanted in the common bile duct on day 14 of pregnancy, and the tip was cut on day 21. [(14)C]Glycocholate (GC) was then administered through the umbilical artery of "in situ" perfused placenta (placental transfer test) or through the maternal jugular vein (biliary secretion test), and GC bile output was measured. OCP impaired both GC placental transfer and maternal biliary secretion. UDCA moderately improved the latter but had a more marked beneficial effect on GC placental transfer. Histological examination revealed trophoblast atrophy and structural alterations, e.g., loss of apical membrane microvilli in OCP placentas. Gene expression level was investigated by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis. OCP reduced both placental lactogen II (a trophoblast-specific gene) mRNA and the functional amount of epithelial tissue, determined by transplacental diffusion of antipyrin. Using a rapid filtration technique, impairment in the ATP-dependent GC transport across trophoblast apical plasma membranes obtained from OCP placentas was found. UDCA partially prevented all these changes. The expression level of organic anion transporters Oatp1, Oatp2, and Oatp4, and multidrug resistance-associated proteins Mrp1, Mrp2, and Mrp3 in whole placenta were not affected or were moderately affected by OCP but greatly enhanced by UDCA. In summary, UDCA partially prevents deleterious effects of OCP on the rat placenta-maternal liver tandem excretory pathway, mainly by preserving trophoblast structure and function.Journal of Pharmacology and Experimental Therapeutics 06/2003; 305(2):515-24. DOI:10.1124/jpet.102.047977