The aim of this study was to identify a subgroup of pregnant women with asymptomatic hypercholanaemia of pregnancy (AHP), in which the relationship between alterations in the level and pattern of serum bile acids (BAs) and of progesterone plus progesterone metabolites could be investigated in the absence of overt impairment of hepatobiliary function. Cholanaemia and serum concentrations of progesterone were assayed by an enzymic technique and by ELISA respectively, while BA molecular species and progesterone metabolites were measured by GC-MS, in the serum of 411 healthy pregnant women. Samples were collected after an overnight fast in the final week of each trimester of gestation. Two pregnant women were excluded because of the suspicion of intrahepatic cholestasis of pregnancy (ICP). Cholanaemia was found to increase progressively throughout pregnancy, but with normal mean values lower than 3.0 microM. Thus in our series AHP was defined arbitrarily as the presence of serum total BA concentrations 2-fold higher than this value, i.e. 6 microM, in the absence of hepatobiliary disease or symptoms of ICP. The prevalence of this condition was observed to increase with gestational age. Changes in the pattern of serum BAs in AHP were also found. These were reflected in a marked increase in the proportion of cholic acid together with a decrease in that of deoxycholic acid, while the proportions of chenodeoxycholic acid and lithocholic acid changed only moderately. When groups at the same gestational age were compared, serum progesterone levels were always significantly lower, while those of progesterone metabolites were higher, in women with AHP. Our results suggest that AHP is a relatively common condition in our geographical location, where ICP is rarely diagnosed. Changes in the serum BA pattern in hypercholanaemia resemble these described in ICP. The simultaneous finding of lower serum total progesterone levels along with an increase in its metabolites supports the hypothesis that a primary defect in progesterone metabolism may be involved in the aetiology of ICP.
Ascorbic acid uptake is a key step in determining the overall bioactivity of this vitamin. Expression of Na-dependent vitamin C transporters (SVCT; SLC23A1 and SLC23A2) during long-term oxidative stress occurring in several chronic liver diseases may determine the antioxidant defence in this organ. In patients with hepatocellular cholestasis, primary biliary cirrhosis, haemochromatosis and non-alcoholic steatohepatitis, using real-time RT-PCR, an enhanced hepatic expression of both SLC23A1 and SLC23A2, but not other organic anions transporters, such as OATP1A2, OATP1B1 and OATP1B3, was found. To further investigate these findings, we used secondary biliary cirrhosis induced in rats by long-term biliary obstruction as a model of chronic liver disease accompanied by oxidative stress because of bile acid accumulation. In control rat liver, expression of Slc23a1 was low at birth, increased progressively up to adulthood and decreased in senescence, whereas expression of Slc23a2 did not change significantly after birth. In 8-week-old rats, immunohistochemistry and confocal microscopy studies revealed the expression in hepatocytes and bile duct cells of mainly Slc23a1, whereas both Slc23a1 and Slc23a2 were expressed in endothelial, stellate and Kupffer cells. In adult rats, when obstructive cholestasis was maintained for 8 weeks, a significant up-regulation of Slc23a2 accompanied by a down-regulation of Slc23a1 was found. In sum, there is a selective cell-type distribution of SVCT in the liver tissue, which, in addition to differential control in the expression of both isoforms, may play a role in the ability of different liver cell types to take up vitamin C under physiological and pathological conditions.
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