Lean liver-disease patients face risks that body weight can obscure

A multinational study published in JAMA on September 30 adds evidence that normal body weight can conceal clinically important metabolic liver disease. Among adults with biopsy-confirmed metabolic dysfunction–associated steatotic liver disease, or MASLD, lean status was not independently associated with lower mortality or major clinical-event risk after adjustment.

The retrospective study included 18,326 adults from 41 countries; 6.7% were lean by body mass index. Although lean participants generally had milder disease, 29.3% had advanced fibrosis, compared with 37.2% of participants with overweight or obesity. Fibrosis means scarring of liver tissue.

Follow-up was available for 9,701 participants over a median of three years. Outcomes included death, liver cancer, hepatic decompensation and transplantation. Advanced fibrosis was associated with approximately twice the adjusted mortality hazard. These findings concern patients with established liver disease, not the risk faced by every person of normal weight.

Why body size can mislead

In an accompanying JAMA editorial, University of Turin gastroenterologist Elisabetta Bugianesi describes several reasons that weight categories provide an incomplete picture. Normal BMI can coexist with fat around internal organs, reduced muscle reserves, insulin resistance and inherited susceptibility to liver injury.

The editorial also highlights imperfect agreement between classifications based on BMI and waist circumference. Both describe aspects of body shape, but neither directly measures the processes that damage the liver. Its interpretation is that metabolic context and fibrosis deserve attention even when a patient does not fit the familiar image of obesity-associated disease.

That distinction matters for healthspan: identifying a disease early enough to prevent complications depends partly on recognizing who may be overlooked. However, the proposed biological explanations remain explanations, rather than mechanisms established by this observational comparison. The analysis does not demonstrate why particular lean participants developed severe disease.

How this fits existing guidance

The American Gastroenterological Association addressed this problem in its 2022 clinical practice update on lean nonalcoholic fatty liver disease, using the terminology then in place. It recommended assessing fibrosis and associated conditions, including diabetes, abnormal blood lipids and hypertension, in affected lean patients.

That guidance distinguished evaluation of a suspected problem from blanket screening. It did not recommend routine screening of all lean adults. It also emphasized excluding alternative causes of liver fat accumulation and using blood-based indices or imaging to help assess fibrosis. Routine genetic testing was not supported by the available evidence.

This context limits an easy misreading of the new results. A finding that body size can obscure risk does not establish that everyone with a normal BMI needs additional testing. Population screening requires separate evidence about benefits, false positives, downstream procedures and costs.

What the evidence leaves unresolved

A retrospective cohort cannot establish that a particular assessment strategy prevents liver failure or extends life. Selecting participants who underwent biopsy also limits how confidently the findings can be applied to people whose disease has never prompted specialist investigation. Incomplete follow-up creates another potential source of bias.

Nor does a statistically nonsignificant difference establish that two groups have precisely identical risks. The practical contribution is narrower: this study strengthens the case for evaluating disease severity directly, while leaving the benefits of specific screening and treatment strategies to further research.