We probed into the potential causal connection between GD and hepatobiliary cancer using MR method. The results showed that GD decreased the risk of having BTC and HCC in an East Asian population. Reverse MR analysis showed that hepatobiliary cancer may both have no effect on the development of GD.
The thyroid hormone 3,3',5-triiodo-L-thyronine (T3) mediates a variety of physiological processes, including regulation of embryonic development, cell differentiation, and cell proliferation. In addition to their developmental and metabolic functions, thyroxine receptor TRs also have tumor inhibitory effects, indicating that their abnormal expression may play a role in promoting tumor transformation[23, 24]. Related studies have further indicated that thyroxine, particularly thyroxine T3, appears to have tumor suppressor properties that inhibit the development of hepatocellular carcinoma cells by improving the duration of the G1 phase of the cell cycle. This property has a connection with reduced expression of the cell cycle medium cyclin-dependent kinase 2 and cyclin E and accelerated gene transcription of the transforming growth factor TGF-β[25]. And thyroid hormones may also inhibit hepatocarcinogenesis through DAPK2 and SQSTM1-dependent optional autophagy[26]. The global prevalence of nonalcoholic steatohepatitis (NASH) is high and is thought to be one of the causes of cirrhosis and hepatocellular carcinoma[27]. Studies have shown that thyroid hormones reduce hepatic steatosis, inflammation, and fibrosis in dietary mouse models of nonalcoholic steatohepatitis, and that activation of thyroid hormone receptors in the liver may help further treatment of NASH[28]. And as a major cause of hyperthyroidism, Graves' disease may have some inhibitory effect on the growth of hepatocellular carcinoma through some pathway, which is consistent with the current Mendelian randomization study.
The literature suggests that non-alcoholic hepatitis may have an effect on biliary tract cancer, especially intrahepatic cholangiocarcinoma, in addition to its possible effect on liver cancer[29, 30]. Because Oddi's sphincter expresses thyroid hormone receptors and thyroxine has a obvious pro-relaxant influence on the sphincter, correlative studies have found that hypothyroidism may promote cholelithiasis formation[31]. Free thyroxine FT4 is an important indicator for diagnosing hyperthyroidism or hypothyroidism. Relevant studies have found that elevated FT4 may promote the formation of cholelithiasis[32]. And it is well known that cholelithiasis is a predisposing factor in the formation of biliary tract cancer. In contrast, studies on the correlation between graves' disease and the progression of cholangiocarcinoma have not yet reported a correlation. The current study is the first to be reported by Mendelian randomization to address the possibility that graves may be a protective factor for cholangiocarcinoma.
Researches on relevance between intestinal microflora and tumors have gradually received[33]. Some studies have even confirmed that certain flora in the intestinal flora may contribute to the formation of gallstone disease. Relevant studies have pointed out that GD can lead to dysbiosis of the intestinal flora, resulting in an increase in some flora, and that dysbiosis of the intestinal flora plays a role in the progression of intrahepatic malignancy (including hepatocyte-derived tumors and tumors originating from cholangiocarcinoma)[34]. In summary, graves' disease may affect the progression of tract hepatocellular carcinoma as well as biliary tract cancer by affecting the intestinal flora. Although there is some basis for these interpretations, deep exploration needed to elucidate the potential principles underlying the status of Graves' disease in biliary tract cancers as well as hepatocellular carcinoma.
Studies have shown that obesity is a risk factor for liver cancer[35]. Excess adipose tissue causes low-grade systemic inflammation through the release of inflammatory cytokines such as IL-6 and TNF, which can lead to chronic liver inflammation, cirrhosis and fibrosis, and tumor necrosis factors[36]. Leptin which is the hormone responsible for feeling full, is excreted when there is too much fat and has been shown to promote the growth of cholangiocarcinoma cells[37]. Patients who suffer from GD results in weight loss due to hormone levels[38].Therefore we can infer that GD may affect hepatobiliary carcinoma by promoting weight loss.
Our study has a number of advantages. Firstly, MR methods tend to have less bias than traditional observational studies when there is unmeasured confounding and reverse causality in the study variables. And it can provide more reliable causality estimates. In fact, several MR methods used in our study yielded consistent outcomes. Second, this study fully excavates publicly available data related to GWAS, and the large sample size of these databases allows us to accurately evaluate the causal relations between variables and obtain greater statistical power. At the same time, there are still several limitations in this study. Firstly, combining statistical methods does not allow us to perform analyses of occurring covariate stratification adjusted by the original GWAS. Secondly, we did not stratify the causal link between GD and hepatobiliary cancer by sex or age. Third, the exposure and outcome analyses included in this study were all from East Asia, and whether the outcomes can be applied to a European population maybe leave over an open question.