Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis

•The bile acid synthesis marker C4 associated negatively with bile acid levels in patients with PSC.•Suppression of bile acid synthesis was likely nearly complete in advanced PSC.•UDCA treatment contributed significantly to total circulating bile acids but did not appear to affect bile acid synthesis.•Attempts to inhibit bile acid synthesis in patients with low C4 may be futile, and such drugs may be contraindicated.•Patients with PSC and low circulating C4 had shorter liver transplantation-free survival in two independent cohorts.