Thyroid dysfunction, either hyper or hypothyroidism, promotes gallstone formation by different mechanisms

Abstract

Abstract:We have investigated comprehensively the effects of thyroid function on gallstone formation in a mouse model. Gonadectomized gallstone-susceptible male C57BL/6 mice were randomly distributed into three groups each of which received an intervention to induce hyperthyroidism, hypothyroidism, or euthyroidism. After 5 weeks of feeding a lithogenic diet of 15% (w/w) butter fat, 1% (w/w) cholesterol, and 0.5% (w/w) cholic acid, mice were killed for further experiments. The incidence of cholesterol monohydrate crystal formation was 100% in mice with hyperthyroidism, 83% in hypothyroidism, and 33% in euthyroidism, the differences being statistically significant. Among the hepatic lithogenic genes, Trβ was found to be up-regulated and Rxr down-regulated in the mice with hypothyroidism. In contrast, Lxrα, Rxr, and Cyp7α1 were up-regulated and Fxr down-regulated in the mice with hyperthyroidism. In conclusion, thyroid dysfunction, either hyperthyroidism or hypothyroidism, promotes the formation of cholesterol gallstones in C57BL/6 mice. Gene expression differences suggest that thyroid hormone disturbance leads to gallstone formation in different ways. Hyperthyroidism induces cholesterol gallstone formation by regulating expression of the hepatic nuclear receptor genes such as Lxrα and Rxr, which are significant in cholesterol metabolism pathways. However, hypothyroidism induces cholesterol gallstone formation by promoting cholesterol biosynthesis.

Assessment of Effects of Thyrotoxicosis on Gallstone Formation in Rabbits

“…The CSI was statistically higher in rabbits receiving thyroxine. As confirmed in this study, it has been shown that thyroid hormones decreases bile acid formation (12,(21)(22)(23). It has been shown that thyrotoxicosis-induced cholesterol gallstones are formed through over-expression of the hepatic nuclear receptor genes, Lxrα and Rxr, which are major components of the cholesterol metabolism pathway (12,24,25).…”

“…The effect of hypothyroidism on gallstone formation is well known (12), but information related to the effects of thyrotoxicosis on gallstone formation is scarce in the literature. In this study, we found an increased risk for gallstone formation in animals with thyrotoxicosis.…”

“…Although some studies have reported a higher prevalence of both hypothyroidism and subclinical hypothyroidism in gallstone patients, which supports a possible relationship between low thyroxine (T4) levels and gallstone disease (12)(13)(14), there are few data regarding the contribution of thyroxicosis to gallstone formation (12).…”

Prevalence and risk factors for gallstone disease: A population‐based cross‐sectional study

“…41 Another study found that the incidence of cholesterol monohydrate crystal formation was higher in both mice with hyperthyroidism and those with hypothyroidism compared with that in control mice. 42 The authors also indicated that hyperthyroidism promoted gallstone formation by regulating the expression of the key regulators of cholesterol metabolism pathway, the hepatic nuclear receptor genes Lxrα and Rxr, while the induction effect of hypothyroidism on cholesterol biosynthesis contributes to development of gallstones in hypothyroid mice. In addition, disorders of bile excretion resulting from the absence of the relaxing effect of thyroxin on the sphincter of Oddi may also be a mechanism whereby hypothyroidism induces gallstones.…”

A family with hypothyroidism caused by fatty acid synthase and apolipoprotein B receptor mutations

“…Two of the main characteristics of hypothyroidism are the marked impairment of lipid metabolism and dyslipidemia ( 9 , 10 ). Furthermore, hypercholesterolemia induces increased concentrations of total and low-density lipoprotein cholesterol ( 11 ), which will affect normal metabolism. At present, the genetic mechanism implicated in the pathogenesis of hypothyroidism remains poorly understood.…”