Interplay of Cardiometabolic Syndrome and Biliary Tract Cancer: A Comprehensive Analysis with Gender-Specific Insights

Abstract

BTC overall incidence is globally increasing. CCA, including its subtypes, is a form of BTC. MetS, obesity, MASLD, and diabetes are all linked to CCA in interconnected ways. The link between obesity and CCA is less well-defined in Eastern countries as compared to Western. Although more research is needed to determine the relationship between MASLD and extrahepatic CCA (eCCA), MASLD may be a concurrent risk factor for intrahepatic CCA, particularly in populations with established or unidentified underlying liver disease. Interestingly, the risk of biliary tract cancer (BTC) seemed to be higher in patients with shorter diabetes durations who were not treated with insulin. Therefore, early detection and prevention of chronic liver disease, as well as additional intervention studies, will undoubtedly be required to determine whether improvements to MetS, weight loss, and diabetes therapy can reduce the risk and progression of BTC. However, further studies are needed to understand how reproductive hormones are involved in causing BTC and to develop consistent treatment for patients. Finally, it is critical to carefully assess the cardiological risk in BTC patients due to their increased intrinsic cardiovascular risk, putting them at risk for thrombotic complications, cardiovascular death, cardiac metastasis, and nonbacterial thrombotic endocarditis. This review aimed to provide an updated summary of the relation between the abovementioned cardio-metabolic conditions and BTC.

Keywords: carcinogenesis; cardiovascular disease; cholangiocarcinoma; gallbladder cancer; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; non-alcoholic fatty liver disease; obesity.

Figure 1

Most prevalent sites of cholangiocarcinoma and gallbladder cancers. CCA: Cholangiocarcinoma; GBC: gallbladder cancer.

Figure 2

Representation of the link and pathogenic factors that connect MetS, MASLD, T2DM, and other chronic liver diseases to BTC and GBC. Biliary tract cancer: MetS, MASLD, T2DM, and hormonal patterns are associated with BTC, in patients with elevated levels of insulin and IGF-1. Especially patients with shorter diabetes periods and naive to insulin had a greater BTC risk. T2DM patients may be affected by insulin’s anabolic effects, which may promote cholestatic cell proliferation. The MAPK pathway mediates insulin’s mitogenic effect. Choledochal cysts or stones, cirrhosis, hepatitis B, and hepatitis C were the most significant risk factors for both iCCA and eCCA. Estrogens play a significant role in BTC onset, likely due to the conversion function of androgenic precursors into estrogens from the adipose tissue aromatase. Obesity causes an alteration in the production of adipokines, particularly leptin and adiponectin. Leptin receptors are highly expressed in metabolically active tissues, whereas adiponectin levels are low. Consequently, malignant transformation enhances the expression of leptin receptors in normal cholangiocytes. MASLD-associated intestinal dysbiosis may promote carcinogenesis by causing leaky gut, microbiome-associated biological patterns, and bacterial metabolites. (*) Aspirin, statins, metformin, and beta blockers have shown promising pleiotropic properties in preventing BTC even by reducing the risk of thrombotic and cardiovascular complications. Intrahepatic cholangiocarcinoma subtype: MetS/MASLD is associated with iCCA risk. In these patients, the liver produces and releases high levels of proinflammatory cytokines, including insulin, IGF, IL-6, MIF, TNF-α, and iNOS, which can promote carcinogenesis. Mice fed a high-fat diet had significantly more severe cholangitis and iCCA than those fed a standard diet. The risk-increasing allele PNPLA3, rs738409, significantly increased the association between MASLD and iCCA. OPN overexpression may cause biliary carcinogenesis in MetS/MASLD patients with iCCA. These triggers can raise the risk of iCCA due to chronic liver inflammation, fibrosis, or cirrhosis. Extrahepatic cholangiocarcinoma subtype: includes perihilar and distal cancers, and is linked to biliary tract diseases. Diabetes, cholecystolithiasis, chronic pancreatitis, and dyslipidemia were all associated with Vater’s ampulla in eCCA. There is a connection between perihilar CCA and PSC. Gallbladder cancer: MetS/MASLD, T2DM, and hormonal patterns increase even the risk of developing GBC. Elevated serum triglyceride levels may be an independent predictor of GBC risk when combined with gallbladder stone disease, while insulin resistance may be the first factor in GBC that is unrelated to gallbladder stone disease. In vitro studies have shown that GBC has elevated levels of insulin receptors and IGF-1 and that gallbladder tumor cells require continuous insulin stimulation to proliferate. Also, reproductive hormones may play a meaningful role in GBC development. Continuous exposure to high levels of female reproductive hormones during pregnancy can lead to gallstone formation. Many GBC patients exhibit ER and PR receptors. Interestingly, postmenopausal women with higher estradiol levels had a significantly higher risk of iCCA. Early hysterectomy and long-term oral contraceptive use were linked to an increase in iCCA risk. MetS: metabolic syndrome; MASLD: metabolic dysfunction-associated steatotic liver disease; T2DM: type-2 diabetes mellitus; BTC: biliary tract cancer; IGF-1: insulin-like growth factor-1; MAPK: mitogen-activated protein kinase; iCCA: intrahepatic cholangiocarcinoma; eCCA: extrahepatic cholangiocarcinoma; FFAs: fatty-free acids; IL-6: interlekin-6; MIF: macrophage migration inhibitory factor; TNF: tumor necrosis factor; iNOS: inducible nitric oxide synthase; PNPLA3: patatin like phospholipase domain containing 3; OPN: osteopontin; GBC: gallbladder cancer; PSC: primary sclerosing cholangitis; ER: estrogen receptor; PR: progesterone receptor.