Relationship between asymptomatic hypercholanaemia of pregnancy and progesterone metabolism

Abstract

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.

Intrahepatic Cholestasis of Pregnancy: The Usefulness of Serum Bile Acid Profile for Diagnosis and Treatment

“…It is suggested that patients could be expectantly managed when TSBA levels remain below 40 µM and when pregnant women refer pruritus it should be surveilled with the aid of repeated determinations of serum bile acids. (Glantz et al, 2004) Recently, a subgroup of asymptomatic pregnant women with high levels of TSBA, and normal liver function tests but not showing pruritus has been classified as asymptomatic hypercholanaemic pregnants (AHP) (Castaño et al, 2006;Lunzer et al, 1986;Pascual et al, 2002;Tripodi et al, 2003). Women with AHP did not differ from normocholanemic women respect to clinical, biochemical or perinatal characteristics.…”

“…It was also demonstrated that the profile of progesterone metabolites in plasma from patients with ICP is markedly different from the profile observed in normal pregnants (Sjövall et al, 1970, Laatikainen et a. 1974Pascual et al 2002).…”

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

“…Silica-based bonded phase cartridges (Sep-Pack Plus C18, Waters, Madrid, Spain) were used to extract bile acids and PMS from 1 ml serum or ≈0.5 g of placental tissue [4]. Methanolic extracts were analyzed using an adaptation [21] of a previously described method for bile acid measurement by HPLC-MS/MS [22] on a 6410 Triple Quad LC/MS device (Agilent Technologies, Santa Clara, CA).…”

“…The risk of these complications is proportional to the degree of maternal hypercholanaemia [3]. In addition to impaired bile acid homeostasis sulphated progesterone metabolites (PMS), whose concentrations are increased even in asymptomatic hypercholanaemia during pregnancy [4], may play a role in ICP owing to their ability to trans-inhibit the bile salt export pump (BSEP) from the canalicular lumen [5]. PMS can also interfere with bile acid homeostasis through interactions with the bile acid nuclear receptor FXR [6].…”

Bile Acid Profiles in Intrahepatic Cholestasis of Pregnancy: Is This the Solution to the Enigma of Intrahepatic Cholestasis of Pregnancy?

“…especially as gestation advances, but these changes have been found to be minimal (9,14,16) . Furthermore, the phenomenon of asymptomatic hypercholanemia, which consists of raised bile acid levels with no associated symptoms or biochemical markers in otherwise healthy pregnant women, has recently been described (17) .…”