Lean People With No Known Risk Factors Can Still Develop Deadly Liver Disease

Fatty liver disease is typically framed as a condition driven by obesity, insulin resistance, and metabolic syndrome. Yet clinicians occasionally encounter lean, apparently healthy patients with unexplained hepatic steatosis — a group that has lacked a clear clinical definition and is often overlooked in research and practice.

This study, published in Gut, sought to characterize 'cryptogenic steatotic liver disease' (SLD), operationally defined as liver fat accumulation in lean individuals (BMI under 25) with no recorded cardiometabolic risk factors. Using the UK Biobank's MRI-based liver fat measurement cohort of nearly 31,000 participants, the researchers found that 3.4% had non-obese SLD. Of these, 13.7% had cryptogenic SLD — meaning no identifiable metabolic drivers. The remaining 86.3% had lean metabolic dysfunction-associated SLD.

Despite the absence of traditional risk factors, cryptogenic SLD was not benign. Affected individuals showed worse liver-related metabolic profiles compared to lean people without liver fat, elevated imaging markers of liver injury, and higher rates of fibrosis on MR elastography. Critically, they were significantly more likely to carry genetic risk variants in PNPLA3 and TM6SF2, genes known to predispose individuals to liver fat accumulation and fibrosis independent of metabolic status.

Longitudinal outcome data from the Korean National Health Insurance Service cohort revealed a hazard ratio of 2.5 for liver-related death in cryptogenic SLD compared to lean, CMRF-free controls. A similar association was found in the UK Biobank cohort, though with wider confidence intervals. These associations persisted after stricter alcohol exclusion, reducing confounding from occult alcohol use.

The implications are significant for clinical practice. Lean, metabolically normal patients are rarely screened for liver disease, yet this study suggests a meaningful subset harbors serious pathology. Clinicians should consider genetic risk profiling and liver imaging even in the absence of conventional metabolic red flags.