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Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum

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Shadi Abu-Hayyeh, Caroline Ovadia, TinaMarie Lieu, Dane D Jensen, Jenny Chambers, Peter H Dixon, Anita Lövgren-Sandblom, Ruth Bolier, Dagmar Tolenaars, Andreas E Kremer, Argyro Syngelaki, Muna Noori, David Williams, Jose J G Marin, Maria J Monte, Kypros H Nicolaides, Ulrich Beuers, Ronald Oude-Elferink, Paul T Seed, Lucy Chappell & 3 more Hanns-Ulrich Marschall, Nigel W Bunnett, Catherine Williamson

Original languageEnglish
JournalHepatology
Volume63
Issue number4
Early online date28 Dec 2015
DOIs
Publication statusPublished - Apr 2016

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Abstract

A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP), or due to benign pruritus gravidarum (PG). ICP is characterised by raised serum bile acids, and complicated by spontaneous preterm labour and stillbirth. A biomarker for ICP would be invaluable for the early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n=35/80, uncomplicated pregnancy=29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from PG (group 2: ICP n=41, PG n=14). In a third group of first trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n=54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice.

CONCLUSION: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP. This article is protected by copyright. All rights reserved.

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