ABSTRACT
UNLABELLED: Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3α-sulfated progesterone metabolites have been shown to be elevated in ICP, leading us to study the impact of sulfated progesterone metabolites on farnesoid X receptor (FXR)-mediated bile acid homeostasis pathways. Here we report that the 3ß-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, coadministration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR, resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using cofactor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of cofactor motifs to the FXR-ligand binding domain. CONCLUSION: Our results reveal a novel molecular interaction between ICP-associated levels of the 3ß-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis.
Subject(s)
Bile Acids and Salts/metabolism , Cholestasis, Intrahepatic/metabolism , Pregnancy Complications/metabolism , Pregnanolone/analogs & derivatives , Progesterone/metabolism , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Sulfuric Acid Esters/blood , Animals , Cholestasis/chemically induced , Cholic Acid , Female , Homeostasis , Humans , Mice , Mice, Inbred C57BL , Phenotype , Pregnancy , Pregnanolone/blood , Receptors, Cytoplasmic and Nuclear/agonistsABSTRACT
BACKGROUND: The literature shows that delayed or erroneous diagnosis of respiratory conditions may be common in primary care due to underuse of spirometry or poor spirometric technique. The Community Respiratory Assessment Unit (CRAU) was established to optimise diagnosis and treatment of respiratory disease by providing focused history-taking, quality-assured spirometry, and evidence-based guideline-derived management advice. AIMS: To review the service provided by the CRAU to primary care health professionals. METHODS: Data from 1,156 consecutive GP referrals over 4 years were analysed. RESULTS: From the 1,156 referrals, 666 were referred for one of five common reasons: suspected asthma, confirmed asthma, suspected chronic obstructive pulmonary disease (COPD), confirmed COPD, or unexplained breathlessness. COPD was the most prevalent referral indication (445/666, 66.8%), but one-third of suggested diagnoses of COPD by the GP were found to be incorrect (161/445, 36%) with inappropriate prescribing of inhaled therapies resulting from this misdiagnosis. Restrictive pulmonary defects (56/666, 8% of referrals) were overlooked and often mistaken for obstructive conditions. The potential for obesity to cause breathlessness may not be fully appreciated. CONCLUSIONS: Misdiagnosis has significant financial, ethical, and safety implications. This risk may be minimised by better support for primary care physicians such as diagnostic centres (CRAU) or alternative peripatetic practice-based services operating to quality-controlled standards.
