Normal BMI Doesn’t Mean Low Risk: Study Links Diabetes to Fatty Liver in Lean Individuals
USA: A Mayo Clinic investigation has revealed that diabetes is the strongest predictor of non-alcoholic steatotic liver disease (SLD) in adults who are not overweight. The research shows that lean individuals with SLD share metabolic and genetic traits that fall between those of healthy lean people and patients with obesity-related SLD, highlighting the need for careful screening even when body weight is normal.
The study, published in Liver International and led by Dr. Karina Sato-Espinoza from the Division of Gastroenterology and Hepatology at Mayo Clinic, examined both clinical and genetic factors that may drive SLD in people with a body mass index (BMI) of 25 kg/m² or less. Researchers analyzed data from 177 lean adults diagnosed with non-alcoholic SLD—47 with cryptogenic SLD and 130 with metabolic-associated SLD (MASLD)—and compared them with 677 lean controls and 3,090 overweight or obese SLD patients drawn from the Mayo Clinic Biobank and Tapestry databases.
The study revealed the following:
- Lean SLD patients showed intermediate rates of diabetes, hypertension, and high cholesterol compared with lean controls and overweight/obese SLD patients.
- They had a mid-range frequency of the PNPLA3 risk allele, a gene variant associated with liver fat accumulation.
- After adjustment for multiple factors, diabetes emerged as the strongest independent predictor of SLD in lean individuals.
- Genetic testing identified subtypes of lean SLD: those with MASLD were more likely to be homozygous for risk alleles in the GCKR gene, linked to metabolic dysfunction and lipid regulation.
- Individuals with cryptogenic SLD, lacking metabolic risk factors, showed no clear genetic markers, leaving the cause of their condition uncertain.
The study also validated the Fib-4 index as a reliable, non-invasive way to detect advanced liver scarring in this unique population. This scoring system, already used for other liver conditions, accurately predicted advanced fibrosis in lean adults with non-alcoholic SLD, offering clinicians a practical tool for early detection of progressive disease.
These results highlight the importance of routine liver health assessments for patients with diabetes, irrespective of body weight. Dr. Sato-Espinoza and colleagues note that physicians should not assume that a normal BMI protects against fatty liver disease or fibrosis. Screening strategies, they suggest, should extend beyond traditional risk groups to capture lean individuals who may otherwise remain undiagnosed.
By clarifying the metabolic and genetic profiles of lean SLD, the research highlights the complex interplay of diabetes, genetic susceptibility, and liver health. It also points to the need for further exploration into cryptogenic cases, where neither metabolic nor genetic risk factors are evident, to better understand the mechanisms driving liver fat accumulation in this subset of patients.
Reference:
Sato-Espinoza, K., Vierkant, R. A., Chotiprasidhi, P., Tian, S., Ma, J., Lazaridis, K. N., Dlugosch, C., Scheider, C., Allen, A. M., & Wangensteen, K. J. (2025). Clinical and Genetic Predictors of Non-Alcoholic Steatotic Liver Disease and Fibrosis in Lean Individuals. Liver International, 45(10), e70300. https://doi.org/10.1111/liv.70300
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