The assumption that body weight reliably predicts cancer risk is increasingly strained — and nowhere more so than in the liver. For most obesity-related malignancies, systemic factors like chronic inflammation, altered hormone signaling, and immune dysregulation create a broadly hostile environment for cellular integrity. The liver, however, operates by a different carcinogenic logic, one that has significant implications for how risk is screened, stratified, and communicated to patients.
A correspondence published in JAMA challenges the pan-cancer obesity framework articulated in a preceding review by Shen and colleagues, specifically regarding hepatocellular carcinoma (HCC). The letter argues that obesity-to-liver-cancer progression is more accurately understood as a sequence of localized metabolic insults — hepatic steatosis, inflammatory activation, fibrogenesis, and progressive architectural remodeling — rather than a consequence of systemic adiposity alone. Critically, BMI may be a poor proxy for this pathway: individuals with equivalent BMI values can carry vastly different degrees of hepatic fibrosis and metabolic dysfunction, leading to divergent HCC risk profiles. Conversely, patients with lower BMI but established metabolic liver disease may face greater hepatocellular cancer risk than heavier individuals without significant liver pathology.
This distinction matters clinically and scientifically. Metabolic dysfunction-associated steatotic liver disease (MASLD) — formerly NAFLD — is now the fastest-growing driver of HCC globally, and a substantial proportion of MASLD-related HCC cases occur in individuals who would not be classified as obese by conventional BMI thresholds. This editorial observation aligns with a growing body of evidence suggesting that visceral adiposity, insulin resistance, and liver stiffness scores are more predictive of HCC development than BMI alone. The practical implication is not yet clinical guidance, but it underscores a measurement gap: population-level cancer risk tools anchored to BMI may systematically underestimate hepatic cancer risk in metabolically compromised individuals of normal or moderate weight. For researchers and clinicians, refining the obesity-cancer framework to incorporate liver-specific metabolic staging — rather than treating the liver as simply another adiposity-exposed organ — may be the next necessary step.