Association of bile acid composition with synthetic pathways and efficacy of bezafibrate in cholestatic liver disease

Abstract

Background/Aims: Bezafibrate (BZF), a dual peroxisome proliferator-activated receptor/pregnane X receptor agonist, has demonstrated efficacy in combination with ursodeoxycholic acid (UDCA) for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Although one of the therapeutic effects of BZF is suppression of bile acid synthesis, its specific impact on bile acid synthesis pathways has not been thoroughly explored. This study investigated bile acid profiles, synthesis intermediates, and their associations with liver biochemistries in patients with PBC and PSC, and evaluated the impact of BZF treatment on these associations. Methods: We enrolled 30 patients with PBC, 10 with PSC, and 30 control subjects. We measured total bile acids, bile acid components, plasma levels of 7α-hydroxycholesterol (7α-OH-C), 7α-hydroxy-4-cholesten-3-one (C4), and 27-hydroxycholesterol (27-OH-C) to assess the classic and alternative bile acid synthesis pathways and analyzed the association with liver biochemistries with and without BZF treatment. Results: Total bile acid levels were elevated in PBC and PSC compared to controls, correlating significantly with liver biochemistries. BZF treatment significantly suppressed the classic pathway, as evidenced by reduced 7α-OH-C and C4 levels. However, 27-OH-C levels, possibly reflecting the alternative pathway activity, were not reduced in those with elevated liver biochemistries despite BZF treatment, suggesting incomplete suppression of alternative pathway in patients with suboptimal BZF response. Conclusions: These findings indicate that while BZF effectively suppresses the classic pathway, alternative pathway activity may compromise its therapeutic efficacy in treatment-resistant cases, highlighting the need for novel therapies inhibiting the alternative pathway in patients with inadequate response to BZF.