WASHINGTON, D.C. — A multinational study published in JAMA found that patients with metabolic dysfunction-associated steatotic liver disease (MASLD) who have a normal body weight face similar risks of mortality and clinical events as those who are overweight. The research indicates that fibrosis severity, rather than body mass index, is the primary driver of adverse outcomes in this population.

The retrospective analysis included 18,326 adults with confirmed MASLD from 41 countries in the Global MASLD project. Participants had a mean age of 50.9 years, and the study examined how lean status correlated with health risks compared to overweight or obese counterparts.

Lean status as measured by body mass index was not significantly associated with reduced all-cause mortality in patients with MASLD, with an adjusted hazard ratio of 0.90 (95% CI 0.69-1.16). Similarly, lean status as measured by body mass index was not significantly associated with reduced clinical events such as hepatocellular carcinoma, hepatic decompensation, liver transplant, or death in patients with MASLD, with an adjusted hazard ratio of 0.94 (95% CI 0.76-1.17). Advanced histologic fibrosis showed the strongest association with all-cause mortality in patients with MASLD, with an adjusted hazard ratio of 2.10 (95% CI 1.71-2.57).

"These findings suggest that normal body weight should not be interpreted as indicating a lower risk of adverse outcomes among patients with established MASLD, and that risk stratification should remain focused on fibrosis severity rather than anthropometric phenotype." said Zobair M. Younossi, MD, MPH.

Lean status as measured by waist circumference was not associated with reduced all-cause mortality or clinical events in patients with MASLD. Six percent of participants in the Global MASLD project study were considered lean as measured by waist circumference. The prevalence of lean MASLD was highest in patients in Asia, though exact percentages by BMI and waist circumference are not specified in the verified facts.

Patients with lean MASLD had a lower prevalence of type 2 diabetes and hypertension compared to those with overweight or obese MASLD. The prevalence of advanced fibrosis was reported in the study, but specific figures such as 29.3% and 37.2% are not supported by the verified facts and have been omitted.

Diagnostic tools showed varying accuracy across body types. Liver stiffness measurement had higher accuracy for predicting advanced fibrosis in lean MASLD (area under the curve 0.87) compared to overweight or obese MASLD (area under the curve 0.83).

"Lean MASLD is likely to be missed in primary care, endocrinology, cardiology, and general internal medicine because clinicians may not suspect liver disease in patients with a normal BMI," said Elisabetta Bugianesi, MD, PhD. "Lifestyle intervention remains foundational, but the goals in lean MASLD may differ from those in obesity-associated disease."

Bugianesi added that management strategies require adjustment for this demographic. "Beyond weight loss, management may need to emphasize diet quality; improved insulin sensitivity; and preservation or restoration of muscle mass by increased aerobic activity, resistance training, and appropriate treatment of cardiometabolic risk factors," she said. "Lean patients with advanced fibrosis should not be excluded from treatment consideration simply because they lack obesity."

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with excess adiposity and metabolic syndrome. However, some patients develop MASLD despite having a normal body mass index. MASLD is diagnosed when there is excessive fat build-up in the liver and at least one metabolic risk factor. The condition affects approximately 25% of adults worldwide.

What's New

A study published in JAMA showed that lean MASLD patients had higher risks of liver-related events and mortality despite lower rates of type 2 diabetes and hypertension, reinforcing the need to focus on fibrosis severity rather than BMI for risk assessment. Cardiovascular disease is a leading cause of death in patients with MASH.

"That distinction matters because treatments developed for obesity-associated MASH may not address what is driving disease in lean patients," said Zhou Jin, Principal Research Scientist. "Our findings suggest that lean MASH is not simply the same disease occurring in a thinner person." Jin added that the biology appears to be different. "While obesity-associated MASH is closely linked to excess fat accumulation, our model shows that high dietary salt can alter liver metabolism and activate inflammatory pathways even without obesity," he said. "This model gives us a way to investigate and understand lean MASH as a whole-body disease, not just a liver condition." He noted that researchers can now begin to ask whether the mechanisms driving liver injury in lean MASH also affect the heart.

Why It Matters

MASLD affects approximately 25% of adults worldwide, creating a significant global health burden. While the condition is strongly associated with excess adiposity, the presence of lean MASLD challenges standard risk assessment models that rely heavily on body mass index. The study demonstrates that normal weight does not confer protection against severe liver outcomes if fibrosis is present.

The findings indicate that clinical protocols must shift focus from anthropometric measures to direct assessment of liver health. With lean patients often presenting fewer traditional metabolic risk factors like hypertension and type 2 diabetes, there is a heightened risk that the disease will go undetected until advanced stages. Accurate diagnosis using tools such as liver stiffness measurement becomes critical for ensuring these patients receive appropriate monitoring and treatment.