Thyroid hormone (TH) deficiency has been associated with increased cholesterol gallstone prevalence. Hypothyroidism impacts hepatic lipid homeostasis, biliary secretion, gallbladder motility and gallstone (LITH) gene expression, i.e. potential factors contributing to cholesterol gallstone disease (CGD). However, how TH deficiency may propel gallstone formation is still poorly understood. Therefore, we performed molecular studies in a CGD mouse model under lithogenic conditions and modulation of TH status.
Male three months old C57BL/6 mice were randomly divided into a control (eu), a hypothyroid (hypo), a gallstone (litho) and a gallstone+hypothyroid (litho+hypo) group and treated for two, four and six weeks (n=8/treatment period). Gallstone prevalence, biliary composition and cholesterol crystals, hepatic expression of genes participating in cholesterol, bile acid (BA) and phosphatidylcholine synthesis (Hmgcr, Cyp7a1, Pcyt1a) and canalicular transport (Abcg5, Bsep, Abcb4) were investigated.
Increased cholesterol gallstone prevalence was observed in hypothyroid mice under lithogenic diet after four and six weeks of treatment (4 weeks: 25% vs. 0%; 6 weeks: 75% vs. 37.5%). Interestingly, neither the composition of the three main biliary components, cholesterol, BAs and phosphatidylcholine nor the hepatic expression of genes involved in synthesis and transport could explain the differences in cholesterol gallstone formation in the mice. However, TH deficiency resulted in significantly increased hydrophobicity of primary BAs in bile. Furthermore downregulation of hepatic sulfonation enzymes Papss2 and Sult2a8 as well as diminished biliary BA sulfate concentrations in mice, were observed under hypothyroid conditions all contributing to a lithogenic biliary milieu as evidenced by microscopic cholesterol crystals and macroscopic gallstone formation.
We describe a novel pathogenic link between TH deficiency and CGD and suggest that the increased hydrophobic character of biliary BAs due to the diminished expression of hepatic detoxification enzymes promotes cholesterol crystal precipitation and finally enhances cholesterol gallstone formation in the bile of hypothyroid mice.