Background: Steatotic Liver Diseases (SLD), defined by excessive hepatic fat accumulation, are the most prevalent chronic liver diseases worldwide. SLD encompasses Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), Metabolic and Alcohol-related Liver Disease (MetALD), and Alcohol-related Liver Disease (ALD). They are driven by metabolic dysfunction (i.e., obesity, insulin resistance, type 2 diabetes, hyperglycemia, hypertriglyceridemia, dyslipidemia, hypertension) or alcohol consumption, or both. SLD often remains clinically silent, and diagnosis relies on invasive biopsy or costly imaging, limiting feasibility in public health and large-scale prospective studies. Evidence suggests SLD are associated with increased cancer risks, particularly colorectal cancer (CRC), but existing studies are restricted to specific populations, limiting generalizability. Validated non-invasive indices, such as the Fatty Liver Index (FLI), are commonly used to estimate hepatic steatosis; however, they depend on availability of key biomarkers (e.g., gamma-glutamyl transferase; GGT).

Objectives: Assess the CRC risk associated with MASLD, MetALD and ALD defined using the FLI, calculated with or without inclusion of GGT measures.

Methods: This analysis used two study populations from the European Prospective Investigation into Cancer and Nutrition (EPIC): (a) a random sub-cohort of 12,692 participants (cases=148; non-cases=12,544) with available GGT measures; (b) a nested case-control study of CRC, including 1,238 incident CRC cases individually matched 1:1 to controls. Hepatic steatosis was estimated using the original Fatty Liver Index (FLI; triglycerides, BMI, waist circumference, GGT) and a weighted version excluding GGT (w-FLI; recalibrated weights for the remaining components). SLD categories were defined as MASLD (hepatic steatosis plus ≥1 metabolic risk factor such as obesity, hypertriglyceridemia, hyperglycemia, dyslipidemia, or hypertension + lower alcohol intake <20g/day for women; <30g/day for men), MetALD (MASLD criteria with moderate alcohol intake: 20–50g/day for women and 30–60g/day for men), and ALD (higher alcohol intake >50g/day for women and >60g/day for men, with or without cardiometabolic risk factors). In the nested case–control study, the same SLD definitions were applied, with hepatic steatosis determined by w?FLI. Associations were estimated using Cox proportional hazards models with Prentice weighting for the case-cohort analysis (Hazard Ratios [HR] and [95% confidence interval]) and multivariable-adjusted conditional logistic regression for the nested case-control analysis (Odds Ratios [ORs] and [95% confidence interval]).

Results: In the case?cohort analysis, FLI and w?FLI were associated with higher CRC risk (HR=1.36 [95%CI=0.89–2.08] and HR=1.23 [95%CI=0.80–1.90]), but confidence intervals included unity. Across SLD categories, hazard ratios increased from MASLD (HR=1.28 [95%CI=0.85-1.91] to MetALD (HR=1.65 [95%CI=0.82-3.29] and ALD (HR=1.76 [95%CI=0.59-5.30]), with confidence intervals overlapping 1.0. When SLD categories were defined using w?FLI, none reached statistical significance (MASLD (HR=1.07 [95%CI=0.70–1.63]), MetALD (HR=1.57 [95%CI=0.76–3.21]), and ALD (HR=1.60 [95%CI=0.49–5.26]). In the nested case–control analysis, w?FLI and MetALD were significantly associated with CRC (OR=1.34 [95%CI=1.07–1.68] and OR=1.69 [95%CI=1.13–2.53]), whereas MASLD and ALD did not reach statistical significance (OR=1.24 [95%CI=0.99-1.54] and OR=1.50 [95%CI=0.83-2.70]).
 

Conclusions: w?FLI produced estimates similar to FLI and was associated with CRC in the case–control design, supporting its application when GGT is unavailable. SLD categories displayed heterogeneous associations across designs, with MetALD being most variable.