Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine

Abstract

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus, elevated bile acids, and, specifically, elevated disulphated progesterone metabolites. We aimed to study changes in these parameters during treatment with dexamethasone or ursodeoxycholic acid (UDCA) in 40 out of 130 women included in the Swedish ICP intervention trial (26 randomized to placebo or UDCA, 14 randomized to dexamethasone). Serum bile acid profiles and urinary steroid hormone metabolites were analyzed using isotope-dilution gas chromatographymass spectrometry and electrospray-mass spectrometry. We found that all patients displayed ICP-typical serum bile acid profiles with >50% cholic acid at baseline but almost 80% UDCA upon treatment with this bile acid. In UDCA-treated patients, relative amounts of disulphated progesterone metabolites in urine decreased by 34%, 48% (P < 0.05), and 55% (P < 0.05) after 1, 2, and 3 weeks of treatment, respectively, which was significantly correlated to improvements of pruritus scores but not to serum bile acid levels. In contrast, in patients randomized to dexamethasone or placebo, no changes in steroid metabolites or pruritus scores were observed. Conclusion: UDCA treatment in ICP decreased urinary excretion of disulphated progesterone metabolites, suggesting that amelioration of pruritus is connected to stimulation of hepatobiliary excretion of progesterone disulphates. I ntrahepatic cholestasis of pregnancy (ICP) is a liver disease of as yet undefined etiology and pathogenesis. ICP is characterized by pruritus and elevated serum bile acids (Ն10 mol/L) with onset in the second half of pregnancy and persisting until delivery. 1 In the observational study of the Swedish ICP intervention trial, 2 the prevalence of pruritus in pregnancy was 2.1%, and that of ICP was 1.5%. Fetal complication rates were related to maternal serum bile acid levels and increased when bile acid levels exceeded 40 mol/L. 2 In the double-blind, placebo-controlled intervention study of the Swedish ICP trial, 3 effects of treatment with dexamethasone, ursodeoxycholic acid (UDCA), or placebo were investigated in 130 patients. UDCA but not dexamethasone significantly reduced alanine aminotransferase and bilirubin in the entire study group and improved pruritus and serum bile acid levels in women presenting with the severe form of ICP with bile acids Ն40 mol/L. 3 Compared with other liver diseases during pregnancy and normal pregnancies, women with ICP have a predominance of cholic acid (CA) among serum bile acids, and specifically, increased levels of steroid monosulphates and disulphates (predominantly progesterone metabolites) in serum and urine (reviewed by Reyes and Sjovall 4 ). Meng and coworkers showed that treatment with UDCA not only lowered plasma bile acid levels but also the levels of sulphated progesterone metabolites, possibly by increasing their hepatobiliary excretion. 5,6 To validate these findings in the Swedish ICP intervention trial population, we analyzed the

Sulfated progesterone metabolites in the pathogenesis of intrahepatic cholestasis of pregnancy: Another loop in the ascending spiral of medical knowledge

“…(3) In the 1990s, a series of reports centered in Sj€ ovall's laboratory, in Stockholm, Sweden, using now more sophisticated and precise techniques applied to serum and urine from Chilean patients with ICP and their controls, clarified that a distinctive biochemical feature in ICP was the switch of progesterone metabolism toward a four-fold to 10-fold increase in serum and urine concentration of sulfated metabolites, with an increased ratio of 3a-hydroxysteroid sulfates to 3b-hydroxysteroid sulfates, changes that were reversed after treatment with ursodeoxycholic acid. (4) Among other important steps in this research line, Glantz et al, in Sweden, reported similar changes in the pattern of progesterone metabolites in urine of ICP patients, with a reversal after ursodeoxycholic acid administration, correlating with an improvement in maternal pruritus (5) ; and Abu-Hayyeh et al also reported increased levels of progesterone sulfates in ICP patients studied in the United Kingdom. (6) Therefore, this metabolic pattern has been detected in ICP patients from different geographic locations and ethnic origins.…”

“…Patients with these characteristics have been identified in several studies, being usually labeled as having pruritus gravidarum (PG), an enigmatic entity that does not carry the fetal risks of a genuine ICP. (5,(9)(10)(11) Table 1 summarizes clinical and biochemical data previously reported in patients with ICP and in normal pregnancies, (7) comparing them with a concurrent unreported cohort of patients with PG in whom pruritus appeared at the same gestational age but was slightly less severe than in patients with ICP. In three of these patients with PG, pruritus diminished spontaneously 1 week prior to delivery; and in another patient, pruritus disappeared in the final week of pregnancy, a phenomenon that was not observed in patients with a genuine ICP.…”

Atopic Eczema and Itch in Pregnancy: Therapeutic Considerations

“…Furthermore, progesterone metabolites are discussed as possible mediators of cholestatic pruritus and of particular interest in cholestasis of pregnancy. Treatment of ICP with ursodeoxycholic acid not only lowers levels of serum bile acids but also of steroid disulfated progesterone metabolites through increased hepatobiliary secretion, which is paralleled by improving pruritic symptoms [11].…”

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

“…Some studies have reported that UDCA administration also reduces maternal plasma concentrations of some PMS [9,10], and this has been related to the improved maternal hepatobiliary function [11]. During intra-uterine life, the placenta is essential for this function in the foetus.…”