Dataset Information

Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol.

ABSTRACT: Cholestatic liver diseases result in the hepatic retention of bile acids, causing subsequent liver toxicity. Peroxisome proliferator-activated receptor alpha (PPARα) regulates bile acid metabolism. In this retrospective observational study, we assessed the effects of fenofibrate (a PPARα agonist) therapy on bile acid metabolism when given to patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) who have had an incomplete response to Ursodiol monotherapy. When fenofibrate was added to Ursodiol therapy there was a significant reduction and in some cases normalization of serum alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase abnormalities, as well as pro-inflammatory cytokines. Combination fenofibrate treatment also reduced 7α-hydroxy-4-cholesten-3-one (C4), the bile acid precursor, as well as total, primary, and conjugated bile acids. In addition, principal components analysis and heatmap analysis show that bile acid metabolites trended closer to that of healthy control subjects. These favorable effects of fenofibrate on bile acid metabolism may contribute to its beneficial clinical effects in patients with PBC and PSC experiencing a subtherapeutic response to Ursodiol monotherapy.

SUBMITTER: Ghonem NS

PROVIDER: S-EPMC7886378 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol.

Ghonem Nisanne S NS Auclair Adam M AM Hemme Christopher L CL Gallucci Gina M GM de la Rosa Rodriguez Randolph R Boyer James L JL Assis David N DN

Clinical pharmacology and therapeutics 20200717 6

Cholestatic liver diseases result in the hepatic retention of bile acids, causing subsequent liver toxicity. Peroxisome proliferator-activated receptor alpha (PPARα) regulates bile acid metabolism. In this retrospective observational study, we assessed the effects of fenofibrate (a PPARα agonist) therapy on bile acid metabolism when given to patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) who have had an incomplete response to Ursodiol monotherapy. When f ...[more]

PMID: 32480421

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Project description:Background & aimsAutoimmune liver disease (AILD) is thought to result from a complex interplay between genetics and the environment. Studies to date have focussed on primary biliary cholangitis (PBC) and demonstrated higher disease prevalence in more urban, polluted, and socially deprived areas. This study utilises a large cohort of patients with PBC and primary sclerosing cholangitis (PSC) to investigate potential environmental contributors to disease and to explore whether the geo-epidemiology of PBC and PSC are disease-specific or pertain to cholestatic AILD in general.MethodsAll adult patients with PBC and PSC in a tightly defined geographical area within the UK were identified. Point- and area-based analyses and structural equation modelling (SEM) were used to investigate for disease clustering and examine for relationships between prevalence, distribution of environmental contaminants, and socio-economic status.ResultsWe identified 2,150 patients with PBC and 472 with PSC. Significant spatial clustering was seen for each disease. A high prevalence of PBC was found in urban, post-industrial areas with a strong coal-mining heritage and increased environmental cadmium levels, whereas a high PSC prevalence was found in rural areas and inversely associated with social deprivation.ConclusionsThis study demonstrates spatial clustering of PBC and PSC and adds to our understanding of potential environmental co-variates for both diseases. Disease clustering, within the same geographical area but over different scales, is confirmed for each disease with distinct risk profiles identified and associations with separate putative environmental factors and socio-economic status. This suggests that different triggers and alternative pathways determine phenotypic expression of autoimmunity in the affected population. Co-variate analysis points towards the existence of specific disease triggers.Lay summaryThis study looked for potential environmental triggers in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) living in the north-east of England and north Cumbria. We found that PBC was more common in urban areas with a history of coal mining and high levels of cadmium whereas PSC was more common in rural areas with lower levels of social deprivation.

Dataset Information

Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol.

Publications

Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol.

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