‘Lean’ MASLD May Sound Better, but Study Suggests Otherwise

While patients with lean metabolic dysfunction-associated steatotic liver disease (MASLD) have less severe histologic disease, they still had a similar risk of adverse clinical outcomes as those with overweight/obese MASLD, according to a multinational retrospective study.

In multivariable models adjusted for country, age, sex, and metabolic comorbidities, lean status as measured by body mass index (BMI) was not significantly associated with reduced all-cause mortality (adjusted HR 0.90, 95% CI 0.69-1.16) or clinical events such as hepatocellular carcinoma, hepatic decompensation, liver transplant, or death (aHR 0.94, 95% CI 0.76-1.17), reported Zobair M. Younossi, MD, MPH, of the Center for Outcomes Research in Liver Diseases in Washington, D.C., and colleagues.

The same was true for lean MASLD as measured by waist circumference, they wrote in JAMA.

Importantly, the strongest association was observed for advanced histologic fibrosis, both with all-cause mortality (aHR 2.10, 95% CI 1.71-2.57) and clinical events (aHR 3.41, 95% CI 2.90-4.03).

The prevalence of advanced fibrosis was 29.3% in patients with lean MASLD versus 37.2% among those with overweight/obese MASLD. The Fibrosis-4 score showed lower accuracy for predicting advanced fibrosis in lean versus overweight/obese MASLD (area under the curve 0.76 vs 0.79), while liver stiffness measurement had higher accuracy (area under the curve 0.87 vs 0.83).

MASLD is strongly associated with excess adiposity and metabolic syndrome, but a subset of patients develop the disease despite having a normal BMI.

“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,” Younossi and colleagues wrote.

In an editorial accompanying the study, Elisabetta Bugianesi, MD, PhD, of the University of Turin in Italy, noted that patients with lean MASLD “reveal the limitations of an obesity-centered clinical approach and ultimately challenge the assumption that normal body weight implies low liver-related risk.”

She suggested the findings have clinical implications in the sense that “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.”

There are also therapeutic implications, Bugianesi added. “Lifestyle intervention remains foundational, but the goals in lean MASLD may differ from those in obesity-associated disease. 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.”

As pharmacologic therapies evolve, “lean patients with advanced fibrosis should not be excluded from treatment consideration simply because they lack obesity,” she wrote, adding that normal weight “should not confer false reassurance, delay fibrosis assessment, or exclude patients from appropriate monitoring and treatment. The future of MASLD care should be phenotype aware, genetically informed, metabolically precise, and fibrosis centered.”

This observational study included 18,326 adults with confirmed MASLD from 41 countries in the Global MASLD project. Mean age was 50.9, and 47.6% were men. About 7% were considered lean as measured by BMI, and 6% were considered lean as measured by waist circumference. The prevalence of lean MASLD was highest in patients in Asia (11.3% by BMI, 11.7% by waist circumference).

Patients with lean MASLD versus overweight/obese MASLD based on both BMI and waist circumference had a lower prevalence of type 2 diabetes and hypertension.

Younossi and team acknowledged that the study had several limitations, including the fact that important determinations of lean MASLD and disease progression — such as detailed diet, physical activity, genetic sequence variants, detailed alcohol exposure, sarcopenia, visceral adiposity, and other body composition measures — were unavailable, meaning residual confounding could not be fully assessed.