Vanishing Bile Duct Syndrome: a model for studying cholestasis related dyslipidemia.

Vanishing bile duct syndrome (VBDS) is characterized by a progressive loss of intrahepatic bile ducts leading to cholestatic end stage liver disease. Its pathogenesis is unclear as well as its link with dyslipidemia. Standardized effective treatments are lacking. Histological and genomic studies were conducted to elucidate the pathogenetic mechanisms in two patients with drug-induced (valproic acid and flucloxacillin) VBDS and severe hypercholesterolemia, while longitudinal lipidomic analysis were performed in order to achieve deeper insights into the correlation between cholestasis and dyslipidemia. Additionally, they both underwent off-label treatments: one with odevixibat, an ileal bile acid transporter inhibitor, and both with fibrates, peroxisome proliferator-activated receptor agonists. In the patient with valproic acid toxicity, genomic analysis revealed a heterozygous mutation in the LSR gene, implicated in intercellular tight junction integrity, as confirmed by electron microscopy findings. Lipid profiling via size-exclusion chromatography and native agarose gel electrophoresis revealed abnormal accumulation of cholesterol either in lipoprotein X or structurally altered HDLs. Moreover, both therapies improved cholestasis and stabilized lipid profiles. These findings suggest a mechanistic model for VBDS involving LSR dysfunction in one case and highlight the need for advanced lipid profiling to better manage the cholestasis-associated dyslipidemia, which is not accurately described by standard biochemistry assays.