Prognostic roles of tetrahydroxy bile acids in infantile intrahepatic cholestasis

Comprehensive bile acid profiling in hereditary intrahepatic cholestasis: Genetic and clinical correlations

“…Consistent with this speculation is the presence of the rarely observed tauro‐THBA in very low concentrations in healthy controls increased by approximately 50‐fold in patients with ABCB11‐ mutations or with genetically undiagnosed cholestasis (Table ). Supporting this observation is a previous report of increased levels of THBAs in the urine of children with intrahepatic cholestasis and better prognoses . The possibility that alternative canalicular transporters other than BSEP might operate is supported by the observation that significant levels of unconjugated secondary bile acids (DCA and LCA) are found in the plasma of the 17 ABCB11 ‐mutated patients (Table ).…”

“…Moreover, the same was true in the plasma of the other 16 ABCB11 ‐mutated patients, 9 of whom were confirmed to have little or no functional BSEP by a lack of BSEP on immunostaining (Table ). Although the sensitivity of immunostaining for BSEP is not known, this procedure readily detects BSEP in the canaliculus of normal liver (Lee et al and Figure ). Taken together, these observations are consistent with the existence of compensatory bile acid metabolism and transport operating in these cholestatic patients.…”

“…Also, metabolic preconditioning of Abcb11 −/− mice involving bile acid hydroxylation appears to protect these mice against acquired cholestatic liver injury such as those resulting from 7 days of common bile duct ligation or 4 weeks of 3.5‐diethoxycarbonyl‐1.4‐dihydrocollidine feeding, conditions that induce cholestasis in wild‐type mice . To what extent similar compensatory mechanisms operate in human cholestatic diseases is unknown although increased levels of THBAs were seen in the urine of a diverse group of infantile intrahepatic cholestatic patients with better prognoses …”

Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2 mice

“…We believe that this is the clearest demonstration to date of the hepatoprotective nature of hydrophilic bile acids. It is noteworthy that reducing the hydrophobicity of the bile acids appears to be a common adaptive reaction to cholestatic stress in patients (52,53).…”

Hepatoprotective impact of the bile acid receptor TGR5

“…The BSEP/abcb11 −/− mice, contrary with the human phenotype of Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2, severe progressive cholestasis in children), only exhibit non‐progressive mild cholestasis, 106 at least in part because their BA pool is less hydrophobic (less toxic), as it is enriched in hyperhydroxylated BA 107 . These BA pool features are now viewed as protective against cholestatic liver injury not only in mice, 106 but also in children with progressive intrahepatic cholestasis 108 . Recent data also pointed out that BA pool composition had impact on alcoholic and non‐alcoholic liver diseases 47,55 .…”