A new study published in JAMA challenges established views about metabolic dysfunction–associated steatotic liver disease (MASLD), demonstrating that individuals with normal body weight face comparable risks to those who are overweight or obese. Researchers analyzed data from 18,326 adults across 41 countries with biopsy-confirmed MASLD, finding that lean patients—defined by a BMI below 25 (or 23 for Asians)—experienced less severe liver disease but similar mortality and complication rates. The findings reveal a long-overlooked subtype of MASLD that current clinical guidelines often miss.
While obesity and type 2 diabetes remain strongly linked to MASLD, the study identified that 6.7% of the cohort had normal weight by BMI, with regional variations: 11.3% in Asia compared to just 2.9% in North America. Waist circumference measurements, available for 12,202 patients, showed only moderate agreement with BMI (κ = 0.41), indicating that BMI alone may not fully capture metabolic risk in some populations. Lean patients displayed milder liver damage overall, with 29.3% showing advanced fibrosis (stages F3-F4) versus 37.2% of overweight or obese patients, and lower NAFLD Activity Scores. However, nearly 3 in 10 patients considered lean had advanced fibrosis, and 11.0% had cirrhosis vs 12.8% of the overweight/obese group.
Over a median follow-up of three years, lean status did not affect death or major complication rates after adjusting for age, sex, and metabolic factors. Instead, fibrosis severity proved the dominant predictor: advanced fibrosis doubled the risk of death and tripled the risk of clinical events, including liver cancer and the need for transplants. Even within the lean group, those with advanced fibrosis faced a 4.24-fold higher risk of complications.
Diagnostic tools fail lean patients
Diagnostic tools showed differing performance in lean patients. The FIB-4 index, commonly used to assess fibrosis, had slightly lower accuracy (AUC 0.76 versus 0.79), while transient elastography (liver stiffness measurement) performed better (AUC 0.87 versus 0.83). The authors attributed these differences to referral biases, noting that lean patients with raised liver enzymes were more likely to undergo biopsy, potentially skewing test results.
The study’s findings create complications for MASLD treatment access. Recent FDA approvals for resmetirom and semaglutide, therapies targeting MASLD with fibrosis, could exclude lean patients if eligibility remains tied to BMI. The research emphasizes the need for broader inclusion in clinical trials and fibrosis-driven care regardless of weight.
Limitations of the study include its biopsy-based design, which may overrepresent severe cases, and missing data on diet, genetics, and body composition. Despite these gaps, the results clearly show that fibrosis, not body weight, determines prognosis, a conclusion that could alter how MASLD is diagnosed and treated.
Metabolic dysfunction, not weight, drives liver damage
Lean MASLD patients differ from their overweight or obese counterparts in metabolic risk factors. While lean individuals had lower rates of type 2 diabetes (38.2% versus 48.3%) and hypertension (42.2% versus 54.5%), their liver disease severity was not proportionally mild. For example, lean patients with advanced fibrosis showed complication risks similar to heavier patients, reinforcing that metabolic dysfunction, not excess body fat, drives liver damage in these cases.
Liver enzyme patterns also varied between groups. Lean patients with MASLD had lower median alanine aminotransferase (ALT) levels (40 U/L) compared to overweight or obese patients (50 U/L), though both groups exceeded normal limits. This referral bias may explain why noninvasive tests like FIB-4 performed differently in lean patients, with lower specificity at standard cutoffs. The authors suggested these discrepancies could reflect how lean patients are identified and evaluated rather than true test accuracy.
The study’s reliance on biopsy data introduced further limitations, as it likely overrepresented patients with advanced disease. Lean patients with mild MASLD may remain undiagnosed or misclassified, given that waist circumference and BMI poorly align (κ = 0.41). In Asia, where lean MASLD prevalence reached 11.3% by BMI and 11.7% by waist, the two measures disagreed in nearly half of cases. This mismatch highlights the need for better screening tools tailored to lean populations, particularly in regions where metabolic risk is underrecognized.
Gaps in screening leave lean MASLD overlooked
Transient elastography proved more reliable than FIB-4 in lean patients, with an AUC of 0.87 compared to 0.76. However, even this test had trade-offs: its specificity for advanced fibrosis was higher (87.6% at 10 kPa), but sensitivity dropped to 69.1% versus 79.1% in overweight or obese patients. The authors cautioned that these variations likely stem from how lean patients are selected for biopsy, often due to abnormal liver enzymes, rather than true disease prevalence. Without broader, non-biopsy-based studies, the generalizability of these findings remains uncertain.
Study Limitations and Treatment Access Implications
Missing information on diet, physical activity, genetic factors, and body composition further restricts broader applicability. Despite these gaps, fibrosis severity remained the key factor in patient outcomes, outweighing body weight in predictive value.
The findings show the need for treatment protocols that prioritize fibrosis assessment over weight-based screening. Clinical trials must expand inclusion to ensure equitable access to emerging therapies.