Abstract:In adults, the hepatobiliary system, together with the kidney, constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine, respectively. However, during intrauterine life the biliary route of excretion for cholephilic compounds, such as bile acids and biliary pigments, is very poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary syst… Show more
“…As previously described in healthy pregnancies [15,25], the transplacental gradient for total bile acids was in the foetus-to-mother direction ( Figure 2A) with a mother : foetus ratio of 0.36. In pregnancies with ICP ( Figure 2B, C), there was a reversal in the gradient resulting in a mother : foetus ratio of 3.1.…”
Section: Relationship Between Cholanaemia In Mothers and Foetusesmentioning
confidence: 74%
“…Bile acids are transferred across the placenta for elimination by the maternal liver. The concerted action of several members of the organic anion transporting polypeptide (OATP) and the ATPbinding cassette (ABC) families located at the foetal and maternal poles of the trophoblast [12,13] accounts for this vectorial transfer (for reviews, see [14,15]). Among transporters involved, ABCG2, also known as breast cancer resistance protein (BCRP), plays a key role [16].…”
AIMIntrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intra-uterine and perinatal complications. High concentrations of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial aetiopathogenesis of ICP. The aim of this study was to investigate further the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio.
METHODUsing HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by real time quantitative PCR (RT-QPCR) and immunofluorescence.
RESULTSIn ICP, markedly increased concentrations of bile acids (tauroconjugates > glycoconjugates >> unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced concentrations in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS concentrations. ABCG2 mRNA abundance was increased in placentas from ICP patients vs. controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2.
CONCLUSIONUDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on concentrations of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high concentrations of bile acids and PMS during ICP.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Intrahepatic cholestasis of pregnancy (ICP) is characterized by an increase in maternal serum concentrations of bile acids and sulphated progesterone metabolites.
WHAT THIS STUDY ADDS• The accumulation of sulphated progesterone metabolites in the serum of ICP patients is associated with enhanced concentrations of progesterone. Although these compounds may be involved in the aetiopathogenesis of ICP, the magnitude of this accumulation does not correlate with the degree of hypercholanaemia in ICP patients.• The beneficial effect of ursodeoxycholic acid (UDCA) treatment includes a reduction of maternal hypercholanaemia, which is not dependent on the correction of progesterone metabolites accumulation.• In spite of marked increases in maternal serum concentrations of sulphated progesterone metabolites and bile acids in ICP patients, the concentrations of these compounds in foetal serum remain normal or are only moderately elevated, respectively. The latter can be corrected by treatment with UDCA.• The ABCG2 export pump located at the apical membrane of trophoblast cells plays an important role in the placental barrier for sulphated progesterone metabolites and bile acids. ABCG2 up-regulation during ICP, and further by UDCA treatment, ...
“…As previously described in healthy pregnancies [15,25], the transplacental gradient for total bile acids was in the foetus-to-mother direction ( Figure 2A) with a mother : foetus ratio of 0.36. In pregnancies with ICP ( Figure 2B, C), there was a reversal in the gradient resulting in a mother : foetus ratio of 3.1.…”
Section: Relationship Between Cholanaemia In Mothers and Foetusesmentioning
confidence: 74%
“…Bile acids are transferred across the placenta for elimination by the maternal liver. The concerted action of several members of the organic anion transporting polypeptide (OATP) and the ATPbinding cassette (ABC) families located at the foetal and maternal poles of the trophoblast [12,13] accounts for this vectorial transfer (for reviews, see [14,15]). Among transporters involved, ABCG2, also known as breast cancer resistance protein (BCRP), plays a key role [16].…”
AIMIntrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intra-uterine and perinatal complications. High concentrations of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial aetiopathogenesis of ICP. The aim of this study was to investigate further the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio.
METHODUsing HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by real time quantitative PCR (RT-QPCR) and immunofluorescence.
RESULTSIn ICP, markedly increased concentrations of bile acids (tauroconjugates > glycoconjugates >> unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced concentrations in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS concentrations. ABCG2 mRNA abundance was increased in placentas from ICP patients vs. controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2.
CONCLUSIONUDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on concentrations of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high concentrations of bile acids and PMS during ICP.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Intrahepatic cholestasis of pregnancy (ICP) is characterized by an increase in maternal serum concentrations of bile acids and sulphated progesterone metabolites.
WHAT THIS STUDY ADDS• The accumulation of sulphated progesterone metabolites in the serum of ICP patients is associated with enhanced concentrations of progesterone. Although these compounds may be involved in the aetiopathogenesis of ICP, the magnitude of this accumulation does not correlate with the degree of hypercholanaemia in ICP patients.• The beneficial effect of ursodeoxycholic acid (UDCA) treatment includes a reduction of maternal hypercholanaemia, which is not dependent on the correction of progesterone metabolites accumulation.• In spite of marked increases in maternal serum concentrations of sulphated progesterone metabolites and bile acids in ICP patients, the concentrations of these compounds in foetal serum remain normal or are only moderately elevated, respectively. The latter can be corrected by treatment with UDCA.• The ABCG2 export pump located at the apical membrane of trophoblast cells plays an important role in the placental barrier for sulphated progesterone metabolites and bile acids. ABCG2 up-regulation during ICP, and further by UDCA treatment, ...
“…Unconjugated bilirubin can cross the placenta, and this is indeed the normal route for excretion during pregnancy as the foetal liver is unable to conjugate or excrete bilirubin (Macias et al 2009;Gajdos et al 2006;McDonagh 2007;2010). It is conceivable that phototherapy of the mother might reduce exposure of the foetal brain to a greater extent than reflected by serum bilirubin levels as the photoisomers of bilirubin are more water soluble and do not cross the blood-brain barrier or presumably the placenta to the same extent as unconjugated bilirubin (Mreihil 2010).…”
During pregnancy, the developing foetus in mothers with Crigler-Najjar type 1 and 2 is exposed to raised levels of unconjugated bilirubin, with the risk of neurotoxicity. We describe two pregnancies in a patient with Crigler-Najjar type 2, who was carefully monitored prior to and during pregnancy and phototherapy adjusted to maintain serum bilirubin levels below 200 mmol/l and the bilirubin/albumin molar ratio below 50%. Both pregnancies resulted in normal delivery of healthy infants who had normal neurological development. A review of all reported pregnancies in Crigler-Najjar patients and a set of recommendations are presented.
“…Although maternal transfer of petroleum hydrocarbons to the developing fetus has been documented in humans, laboratory animals, and sea otters during the Exxon-Valdez oil spill (Tuomi and Williams, 1995;Perera et al, 1999;Tozuka et al, 2004), little is known about fetal metabolism of these compounds. During human fetal development, the immature hepatobiliary excretory system is not yet functional, so the placenta functions to metabolize and excrete toxins back to the maternal system for elimination and also acts as a barrier to protect the fetus from potentially toxic compounds in maternal blood (Macias et al, 2009). However, if one or both of these mechanisms is impaired or overwhelmed by an acute exposure, toxins could enter fetal circulation, resulting in deleterious effects to the fetus (Macias et al, 2009).…”
mentioning
confidence: 99%
“…During human fetal development, the immature hepatobiliary excretory system is not yet functional, so the placenta functions to metabolize and excrete toxins back to the maternal system for elimination and also acts as a barrier to protect the fetus from potentially toxic compounds in maternal blood (Macias et al, 2009). However, if one or both of these mechanisms is impaired or overwhelmed by an acute exposure, toxins could enter fetal circulation, resulting in deleterious effects to the fetus (Macias et al, 2009). A large bunker fuel spill (58,000 gallons) occurred in San Francisco Bay in November 2007, which corresponds roughly with the late first trimester to early second trimester of this pup's gestation (Reidman, 1990); however, exposure may have occurred from petroleum products that entered the bay via nonpoint-source discharges.…”
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