Clinical data and murine studies suggest an association between hypothyroidism and cholesterol gallstone disease (CGD). Moreover, although women are more prone to both disorders, CGD and hypothyroidism, the retrospective study from Völzke et al. revealed increased cholesterol gallstone prevalence under hypothyroidism predominantly in men. However, the precise underlying molecular mechanisms are still poorly understood.

In order to investigate the impact of hypothyroidism on cholesterol gallstone formation, three months old male and female C57BL/6J mice were fed a lithogenic diet either under euthyroid or hypothyroid condition for 2, 4 and 6 weeks. The findings of the present study indicate that hypothyroidism promotes CGD by increased hydrophobicity of primary bile acids due to altered hepatic detoxification phase II processes. In particular, the gene expression of hepatic sulfonation enzymes Papss2 and Sult2a8/Sult2a1 was diminished in hypothyroidism leading to reduced biliary concentration of the hydrophilic sulfated bile acid derivates and consequently to a more lithogenic biliary milieu. The observed male predominant prevalence of CGD seems to result from the reduced biliary water transport in hypothyroidism due to diminished Aqp1 and Aqp8 expression and Aqp1 translocation in gallbladders from epithelial cells to subcellular vesicles.

Moreover, the findings of present study show the impact of hypothyroidism on hepatic lipid droplet (LD) morphology and the gene expression of LD-associated proteins, underlining the relevance of the thyroid hormone status on the liver metabolic state and function.

In conclusion, a novel pathogenic link between CGD and TH deficiency, including TH-dependent alterations of 1) the hepatic detoxification system, 2) the biliary water transport and 3) the molecular LD properties, is described in present study. These findings may contribute significantly to the understanding of CGD and further severe liver diseases, e.g. non-alcoholic fatty liver disease (NAFLD).