Relationship between early onset severe intrahepatic cholestasis of pregnancy and higher risk of meconium-stained fluid.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disease. The risk of adverse fetal outcome has been associated with the severity of maternal hypercholanemia after diagnosis. OBJECTIVE: To investigate whether there is a relationship between the severity and timing of onset of hypercholanemia and the risk of meconium-stained amniotic fluid (MSAF) and adverse neonatal events. STUDY DESIGN: The study included 382 pregnancies complicated by ICP managed at a referral hospital in Buenos Aires (Argentina) between June 2009 and December 2013. The patients were classified into three groups according to the severity of hypercholanemia at diagnosis; mild (10-19.9 µmol/L), moderate (20-39.9 µmol/L) and severe (≥40 µmol/L). Their clinical characteristics and pregnancy outcomes were investigated in a prospective observational study. RESULTS: Higher risk of MSAF was observed when ICP appeared early in gestation or when hypercholanemia was more severe. Taking both parameters into account an MSAF risk factor (MRF) was defined. Based on a model of positive/negative predictive values, a cut-off point of MRF = 3 was selected, which prioritized sensitivity versus specificity. In ICP patients with MRF>3, the probability of MSAF was enhanced 4-fold. An increase in the frequency of MSAF was also associated with higher serum levels at diagnosis of alanine transaminase, alkaline phosphatase and direct bilirubin. CONCLUSIONS: The risk of MSAF is associated not only with the magnitude of hypercholanemia at diagnosis but also with the early gestational onset of raised maternal serum bile acids.

Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother-placenta-foetus trio during cholestasis of pregnancy.

AIM: Intrahepatic 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. METHOD: Using 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. RESULTS: In 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. CONCLUSION: UDCA 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.

Acetaminophen-induced stimulation of MDR1 expression and activity in rat intestine and in LS 174T human intestinal cell line.

The well-known analgesic and antipyretic drug N-acetyl-p-aminophenol (acetaminophen; APAP) has been previously reported to affect MDR1 expression in rat liver. In this study, we have investigated the effect of subtoxic doses of APAP on MDR1 expression and activity in rat intestine and human intestinal cells. Administration of APAP at increasing doses of 0.2, 0.3, and 0.6g/kg b.w., i.p. over three consecutive days, induced MDR1 expression in rat duodenum (+240%) and ileum (+160%) as detected by western blotting. This was accompanied by preserved localization of the protein at the surface of the villus, as detected by confocal immunofluorescence microscopy. MDR1 activity was increased by 50% in APAP treated rats, as evaluated by serosal to mucosal secretion of rhodamine 123 in everted intestinal sacs. Treatment with APAP also decreased by 65% the portal vein concentrations of digoxin found in anesthetized rats after intraduodenal administration of this drug, which is consistent with an APAP-induced increased efficacy of intestinal barrier for digoxin net absorption. Exposure of LS 174T human colon adenocarcinoma cells to subtoxic APAP concentration (5mM) induced an increase in MDR1 mRNA expression (+46%), which was accompanied with an enhanced ability (+78%) to reduce intracellular content of rhodamine 123. Taken together these data suggest the existence of APAP-induced stimulation of MDR1 transcription in the intestinal epithelium. These findings are of clinical relevance, as co-administration of APAP with other MDR1 substrates could indirectly inhibit the net intestinal absorption of these drugs, leading to changes in their pharmacokinetics and therapeutic efficacy.

Molecular pathogenesis of intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) occurs mainly in the third trimester and is characterised by pruritus and elevated serum bile acid levels. ICP is associated with an increased perinatal risk and higher rates of foetal morbidity and mortality. Although the pathogenesis of this disease is unknown, a genetic hypersensitivity to female hormones (oestrogen and/or progesterone) or their metabolites is thought to impair bile secretory function. Recent data suggest that mutations or polymorphisms of genes expressing hepatobiliary transport proteins or their nuclear regulators may contribute to the development and/or severity of ICP. Unidentified environmental factors may also influence pathogenesis of the disease. This review summarises current knowledge on the potential mechanisms involved in ICP at the molecular level.

Molecular bases of the excretion of fetal bile acids and pigments through the fetal liver-placenta-maternal liver pathway.

Since the excretion of potentially toxic cholephilic organic anions (COAs) produced by the fetus, such as bile acids and biliary pigments, cannot be performed by the fetal liver alone, the placenta and the maternal liver must play a key role collaborating in this function. COAs are transported across the plasma membranes of fetal and maternal hepatocytes and trophoblastic cells via similar carrier proteins. OATPs (organic anion-transporting polypeptides), mainly OATP1B1 and OATP1B3 are involved in COA uptake across the basal membrane of adult hepatocytes and trophoblastic cells. Certain OATPs may also play a role in COA efflux from fetal hepatocytes toward the fetal blood and from the trophoblast to the maternal blood. Either unmodified or biotransformed during their transit across the placenta, COAs are transferred to the maternal blood by MRPs (multidrug resistance-associated proteins), such as MRP1, MRP2 and MRP3. BCRP (breast cancer resistance protein) may also be involved in this step. Under physiological circumstances, fetal COAs are taken up by the maternal liver, which eliminates them across the canalicular membrane via MRP2 and BSEP (bile salt export pump). However, when normal biliary excretion is not possible, the accumulation of COAs, in particular in the fetal liver, placenta and maternal liver trio, induces oxidative stress and apoptosis, which has noxious repercussions on normal fetal development and even challenges pregnancy outcome. Treatment of pregnant rats with ursodeoxycholic acid, even though maternal hypercholanemia is not corrected, prevents oxidative damage and the subsequent deleterious effects on the placenta and fetal liver.

Bases moleculares de la función excretora de tipo hepatobiliar de la placenta / Molecular basis of excretory function placental hepatobiliary type

The liver plays an important excretory role eliminating from the body potentially toxic compounds that are xenobiotics or produced endogenously, such as bile acids and biliary pigments. This involves both transport and biotransformation processes. During intrauterine life, the inmature fetal liver cannot carry out this function. Therefore, the placenta performs a hepatobiliary-like excretory role, transferring cholephilic compounds from the fetus to the mother. The similarity of this function in the placenta and the adult liver is probably accounted for by the presence in both organs of proteins of the OATP family, involved in the uptake of organic anions across the basolateral membrane of several epithelia, and of members of the superfamily of ATP-binding cassette (ABC) proteins, which are involved in the export of substances out of many different cells. Thus, several studies have shown that, in addition to a difussional component, that may become particularly important for unconjugated bilirubin, the main mechanisms for bile acids and bilirubin transplacental transfer from the fetus to the mother are carrier-mediated transport systems, which have vectorial properties and also play an important role in the placental barrier by preventing or reducing the net flux of noxious substances from the mother to the fetus.

El hígado juega un papel determinante en la excreción de sustancias potencialmente tóxicas de origen externo o producidas por el organismo, como ácidos biliares y bilirrubina. Esta función implica tanto procesos de transporte como de biotransformación. Durante la vida intrauterina, el hígado fetal no es aún capaz de realizar esta función, por lo que es la placenta la que asume un papel excretor similar al que desempeña el sistema hepatobiliar en el adulto. La similitud entre ambas funciones se debe a la presencia en ambos órganos de proteínas transportadoras de la familia OATP, que llevan a cabo la captación de aniones orgánicos en varios epitelios, y de miembros de la superfamilia de proteínas ABC ("ATP-binding cassette"), capaces de bombear al exterior celular una gran variedad de sustancias. Estudios recientes demostraron que, además de un componente difusional, que es más relevante en el caso de la bilirrubina no conjugada, la vía mayoritaria en la transferencia placentaria de ácidos biliares y bilirrubina está mediada por sistemas de transporte que, en conjunto, presentan características de vectorialidad feto-materna, y que por ello también juegan un papel en la barrera placentaria reduciendo el flujo de sustancias nocivas desde la madre al feto.