Lean MASLD Carries Similar Risk as Overweight, Obese Disease

Patients with lean metabolic dysfunction–associated steatotic liver disease (MASLD) had less severe liver histology than those considered overweight or obese, but they faced a similar risk of death and serious liver complications, with prognosis associated with fibrosis severity rather than body weight, according to a recent study published in JAMA.¹

Why Lean MASLD Has Been Difficult to Characterize

Although MASLD is closely tied to obesity and type 2 diabetes, a subset of patients develops the disease at a normal body mass index (BMI). Prior studies of this lean phenotype have been small, single-center, or based on imaging rather than biopsy. They have also reached conflicting conclusions about whether these patients have milder or more severe liver disease. In addition, it has been unclear how well common noninvasive fibrosis tests perform in this group.

To address these gaps, investigators analyzed data from the Global MASLD (G-MASLD) project, an international biopsy-based cohort coordinated by the Global NASH/MASH Council. The study included 18,326 adults with histologically confirmed MASLD from 41 countries. The cohort defined lean status by either BMI (below 25; below 23 for Asian patients) or, among 12,202 patients with available measurements, by sex- and ethnicity-specific waist circumference thresholds.

Lean Patients Had Milder Disease but Substantial Fibrosis

Overall, 6.7% of the 18,326 patients were considered lean by BMI, compared with 6.0% of the 12,202 assessed by waist circumference. However, agreement between the 2 definitions was only moderate (κ = 0.41), which the authors said reflects the limitations of BMI alone as a marker of metabolic risk. Lean MASLD was most common among patients enrolled in Asia (11.3% by BMI; 11.7% by waist circumference) and least common in North America (2.9%; 1.6%).

Compared with patients considered overweight or obese, lean patients had lower rates of type 2 diabetes (38.2% vs 48.3%) and hypertension (42.2% vs 54.5%). Their histology was also less severe, with advanced fibrosis (stage F3-F4) in 29.3% vs 37.2% and lower mean (SD) Non-Alcoholic Fatty Liver Disease Activity Scores (3.96 [1.81] vs 4.41 [1.68]), driven mainly by less lobular inflammation and hepatocyte ballooning. Still, nearly 3 in 10 patients considered lean had advanced fibrosis, and 11.0% had cirrhosis vs 12.8% of the overweight/obese group.

Fibrosis, Not Body Weight, Tracked With Outcomes

Among 9701 patients followed for a median of 3 years after biopsy, 526 died, and 756 experienced a clinical event, defined as hepatocellular carcinoma, hepatic decompensation, liver transplant, or death. After adjusting for country, age, sex, and metabolic comorbidities, lean status was not associated with all-cause mortality (adjusted HR [aHR], 0.90; 95% CI, 0.69-1.16) or clinical events (aHR, 0.94; 95% CI, 0.76-1.17). Results were consistent using the waist circumference definition, across regions, and in a sensitivity analysis imputing missing waist data.

By contrast, advanced fibrosis was associated with roughly double the risk of death (aHR, 2.10; 95% CI, 1.71-2.57) and more than triple the risk of clinical events (aHR, 3.41; 95% CI, 2.90-4.03). Within the lean group alone, advanced fibrosis carried an aHR of 4.24 (95% CI, 2.48-7.24) for clinical events.

Test performance also differed by body type. The Fibrosis-4 (FIB-4) index was somewhat less accurate in lean patients (area under the curve [AUC], 0.76 vs 0.79), with lower specificity at the common 1.30 cutoff (63.7% vs 72.2%). Liver stiffness measurement by transient elastography performed better in lean patients (AUC, 0.87 vs 0.83), with a specificity of 87.6% vs 70.8% at a 10-kPa threshold; however, sensitivity was lower (69.1% vs 79.1%).

“It is also important to note that in this biopsy-based sample, reduced accuracy of FIB-4 in lean patients may partly reflect referral and/or biopsy selection patterns because lean individuals may be more likely to undergo specialty evaluation and biopsy when aminotransferase levels are elevated,” the authors wrote. “This could shift FIB-4 upward without a proportional increase in histologic fibrosis severity and may not reflect FIB-4 performance in lower-risk, unselected lean MASLD populations.”

Where the Findings Fit in MASLD Care

The results add nuance to FIB-4, a low-cost test that some experts say remains underused in primary care and obesity medicine.² The findings may also have implications for treatment access among lean patients, particularly with the recent FDA approvals of resmetirom (Rezdiffra; Madrigal Pharmaceuticals) and semaglutide (Wegovy; Novo Nordisk) for metabolic dysfunction–associated steatohepatitis with moderate to advanced fibrosis.^3,4 The authors noted that lean patients have been underrepresented in MASLD trials, calling for their inclusion and for approved therapies to be applied without BMI-based restrictions.¹

The authors acknowledged their study’s limitations, including that the biopsy-based design likely overrepresents patients referred for suspected advanced disease, limiting generalizability to lower-risk populations.¹ In addition, waist data were incomplete, and the dataset lacked information on diet, physical activity, genetic variants, and body composition. Still, they emphasized that prognosis was associated with fibrosis severity rather than body habitus.

“…fibrosis-based assessment and management strategies should be applied consistently in all patients with MASLD, regardless of BMI or weight,” the authors concluded.

References

1. de Avila L, AlNaamani KM, Papatheodoridi M, et al. Histologic features and clinical outcomes of lean metabolic dysfunction–associated steatotic liver disease. JAMA. Published online September 30, 2026. doi:10.1001/jama.2026.18491
2. Joszt L, Alkhouri N, Anekwe C. Closing the liver detection gap in obesity care. AJMC^®. June 30, 2026. Accessed October 7, 2026. https://www.ajmc.com/view/closing-the-liver-detection-gap-in-obesity-care
3. Joszt L. FDA approves resmetirom, first treatment for NASH with liver fibrosis. AJMC. March 14, 2024. Accessed October 7, 2026. https://www.ajmc.com/view/fda-approves-resmetirom-first-treatment-for-nash-with-liver-fibrosis
4. Klein HE. FDA approves semaglutide for MASH with fibrosis. AJMC. August 18, 2025. Accessed October 7, 2026. https://www.ajmc.com/view/fda-approves-semaglutide-for-mash-with-fibrosis