Metabolic dysfunction-associated steatotic liver disease and the consequence of extra-hepatic malignancy

Table 1 Gastrointestinal extrahepatic malignancies in metabolic dysfunction-associated steatotic liver disease: Cancer type, key studies, risk estimates, proposed mechanisms, and trends

Cancer type	Ref.	Risk estimate (HR or OR)	Proposed mechanisms	Trend/notes
Colorectal cancer	Wu et al[33], 2026 (international Delphi consensus, Gut); Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis, n ≈ 16.7M); Allen et al[35], 2019 (community cohort, J Hepatol); Azimi et al[34], 2025 (meta-analysis, n > 56M)	HR 1.33 (Zhou et al[37] meta-analysis); approximately 1.5-2-fold (Mantovani et al[12], 2022); OR 1.37 (Azimi et al[34], 2025)	Gut dysbiosis; secondary bile acid alterations; hyperinsulinemia; mucosal inflammation; IGF-1 axis activation	Rising; strongest GI cancer association; independent of obesity and T2DM
Pancreatic cancer	Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis, Eur J Clin Invest); Thomas et al[9], 2024 (review, Lancet GE&H); Thomas et al[10], 2022 (meta-analysis, Eur J Cancer); Mantovani et al[36], 2024	HR 1.41 (Zhou et al[37] meta-analysis); approximately 1.5-2-fold (Mantovani et al[12], 2022)	Insulin resistance; visceral adiposity; acinar inflammation; shared T2DM pathway	Rising; evidence strengthening with larger population cohorts
Esophageal/gastric cancer	Zou et al[40], 2023 (meta-analysis); Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Thomas et al[9], 2024 (Lancet GE & H); Mantovani et al[36], 2024	Gastric: HR 1.47 (Zhou et al[37]), RR 1.49 (Zou et al[40]); esophageal: RR 1.76 (Zou et al[40]), null in Zhou et al[37] meta-analysis	GERD; Barrett’s esophagus; visceral adiposity; reflux-related mucosal injury	Moderate; gastric cancer signal more consistent than esophageal across meta-analyses
Biliary tract cancer (gallbladder/cholangiocarcinoma)	Park et al[41], 2021 (nationwide Korean cohort, n ≈ 8.1M, Eur J Cancer); Zhou et al[37], 2024 (meta-analysis); Mantovani et al[36], 2024	BTC overall: AHR 1.28 (Park et al[41], 2021), HR 1.27 (Zhou et al[37]); cholangiocarcinoma aHR 1.33; gallbladder aHR 1.14	Biliary stasis; cholelithiasis; chronic biliary inflammation	Emerging; cholangiocarcinoma shows the stronger signal; gallbladder signal weaker; Western validation limited

HR: Hazard ratio; OR: Odds ratio; aHR: Adjusted hazard ratio; RR: Relative risk; IGF-1: Insulin-like growth factor-1; T2DM: Type 2 diabetes mellitus; GERD: Gastroesophageal reflux disease; BTC: Biliary tract cancer; GI: Gastrointestinal.

Table 2 Non-gastrointestinal extrahepatic malignancies in metabolic dysfunction-associated steatotic liver disease: Cancer type, key studies, risk estimates, proposed mechanisms, and trends

Cancer type	Ref.	Risk estimate (HR or OR)	Proposed mechanisms	Trend/notes
Breast cancer	Lee et al[51], 2026 (nationwide Korean cohort); Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Thomas et al[9], 2024 (Lancet GE & H); Zhang and Nguyen[26], 2025 (review)	HR 1.17 (Zhou et al[37] meta-analysis); HR 1.20 in postmenopausal women with BMI 25-30 (Lee et al[51], 2026); OR approximately 1.2-1.5 (Mantovani et al[12], 2022)	Peripheral estrogen excess; leptin signaling; IR-IGF-1 axis; adipokine dysregulation	Rising; highest-burden non-GI cancer association; postmenopausal women at greatest risk
Endometrial cancer	Allen et al[35], 2019 (community cohort, J Hepatol); Mantovani et al[12], 2022 (meta-analysis, Gut); Thomas et al[10], 2022 (meta-analysis, Eur J Cancer); Thomas et al[9], 2024 (Lancet GE & H); Zhang and Nguyen[26], 2025 (review)	Approximately 2-fold uterine cancer risk in NAFLD (Allen et al[35], 2019); pooled OR approximately 1.5-2.1 across studies	Unopposed estrogen stimulation; hyperinsulinemia; adipokine excess	Rising; strong mechanistic plausibility; consistent across populations
Ovarian cancer	Park et al[46], 2025 (nationwide Korean cohort, n = 2.3M women, ages 20-39); Zhou et al[37], 2024 (meta-analysis); Zhang and Nguyen[26], 2025 (review, Metabolism)	HR 1.30 young-onset ovarian cancer (Park et al[46], 2025); HR 1.36 female genital organ cancers (Zhou et al[37] meta-analysis)	Hormonal dysregulation; PCOS overlap; adipokine signaling	Emerging; young-onset data of concern; limited overall evidence base
Thyroid cancer	Moon et al[47], 2025 (Korean cohort, thyroid); Zhou et al[37], 2024 (meta-analysis); Chen et al[49], 2025 (meta-analysis); Kwon et al[48], 2024 (cohort); Liu et al[43], 2022 (metabolism)	HR 1.36 (Moon et al[47], 2025); HR 1.46 (Zhou et al[37] meta-analysis); HR 1.69 in women (Liu et al[43], 2022 United Kingdom Biobank)	Insulin resistance; TSH dysregulation; thyroid nodularity in MASLD	Emerging; predominantly Asian cohort data; Western validation needed
Urinary system cancer (renal cell/bladder)	Bril and Elbert[68], 2025 (review); Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Thomas et al[10], 2022; Thomas et al[9], 2024	HR 1.45 (Zhou et al[37] meta-analysis); OR approximately 1.2-1.5 (Mantovani et al[12], 2022); kidney/bladder cancers documented in pooled NAFLD incidence data	Adiposity-driven ROS; chronic renal inflammation; altered adipokine signaling	Underexplored; mechanistically plausible; dedicated studies lacking
Lung cancer	Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Pan et al[69], 2025 (review); Thomas et al[9], 2024 (Lancet GE & H)	OR approximately 1.2-1.5 (Mantovani et al[12], 2022); null association in Zhou et al[37], 2024 meta-analysis	Systemic inflammation; adipokine-mediated bronchial epithelial effects; shared metabolic exposures	Mixed; signal present in some cohorts but null in pooled analyses; smoking confounding remains a key concern
Prostate cancer	Mantovani et al[12], 2022 (meta-analysis, Gut); Zhou et al[37], 2024 (meta-analysis); Thomas et al[10], 2022 (meta-analysis, Eur J Cancer); Thomas et al[9], 2024 (Lancet GE & H)	Conflicting; null in pooled meta-analyses (Mantovani et al[12], 2022; Zhou et al[37], 2024); inverse association reported in some Korean cohorts	Testosterone deficiency may reduce androgen-driven risk; complex hormonal interplay in MASLD/obesity	Uncertain; inverse/null in most studies; mechanism warrants further investigation

HR: Hazard ratio; OR: Odds ratio; IR: Insulin resistance; IGF-1: Insulin-like growth factor-1; BMI: Body mass index; TSH: Thyroid-stimulating hormone; PCOS: Polycystic ovarian syndrome; ROS: Reactive oxygen species; GI: Gastrointestinal; NAFLD: Non-alcoholic fatty liver disease; MASLD: Metabolic dysfunction-associated steatotic liver disease.