Background
Metabolic dysfunction in the liver is influenced by various factors, including abdominal obesity, dyslipidaemia (elevated triglyceride concentrations and reduced HDL-C concentrations), hypertension, and fasting hyperglycaemia or type 2 diabetes which are also key components of metabolic syndrome (MetS), a clustering of cardiometabolic abnormalities that markedly increases the risk of systemic insulin resistance and related metabolic diseases, including some cancers. These abnormalities contribute to impaired hepatic lipid and glucose metabolism, which are major drivers of hepatic fat accumulation and progressive liver injury leading to steatotic liver diseases (SLD) along with likely increased risks for cancer development. Previously termed non-alcoholic fatty liver disease (NAFLD), SLD is now an umbrella term covering metabolic dysfunction associated SLD (MASLD; steatosis with at least one cardiometabolic abnormality; low alcohol intake) and alcohol related subtypes, namely metabolic dysfunction–associated alcohol related liver disease (MetALD; moderate alcohol consumption) and alcohol related liver disease (ALD; high alcohol intake with or without metabolic abnormalities). Robust data from prospective cohort studies on associations of MetS and SLD with risk of hepatobiliary cancers (HBC) is lacking.
 
Objectives
To assess the association of MetS and SLD with different HBC anatomical sites including hepatocellular carcinoma (HCC), intrahepatic bile duct (IBD), extrahepatic bile duct (EBD), ampulla of Vater (AOV), and gallbladder cancers (GBC) in the large, prospective EPIC cohort.
 
Methods
Individual case-control studies (1:1 matching) were nested within EPIC for each anatomical site. After >17 years of follow-up, a total of 204 HCC, 56 IBD, 63 EBD, 47 AOV and 61 GBC cases were identified from 387,889 eligible participants with available biospecimens. Composite variables for MetS, based on the international diabetes federation (IDF) established definition, were created from 5 individual components (abdominal obesity, elevated blood pressure, elevated triglycerides, reduced HDL-C cholesterol, and abnormal glucose metabolism).  The fatty liver index (FLI) was calculated to assess the presence of SLD. The association between MetS, its individual components, and each SLD with cancer risk at each anatomical site was assessed using multivariable-adjusted conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI).
 
Results
Increased HCC risk was observed for MetS (OR=1.70, 95%CI:1.08– 2.68) and its individual components of abdominal obesity (OR=2.19, 95%CI: 1.43–3.53), elevated blood pressure (OR=1.17, 95%CI: 0.70–1.9), abnormal glucose metabolism (OR=1.39, 95%CI: 0.88–2.22), and reduced HDL-C cholesterol (OR=1.25, 95%CI: 0.80–1.97), but not elevated triglycerides (OR=1.02, 95%CI: 0.64–1.63). Increased HCC risk was observed for NAFLD (OR=4.01, 95%CI: 2.24–7.18), MASLD (OR=5.39, 95%CI: 2.67–10.89), MetALD (OR=2.45, 95%CI: 1.09–5.50), and ALD (OR=14.46, 95%CI: 3.14–66.61). No significant associations were observed between MetS, any SLD and risk of other hepatobiliary cancer types.
 
Conclusions
These findings based on data and blood samples collected several years prior to cancer diagnosis show that metabolic dysfunction, abdominal obesity and SLD play strong roles in HCC development.