The generalizability of our findings is limited by the characteristics of the UK Biobank

The gap

Evidence profile

Sourced from the future work and recommendations and conclusions and limitations section of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 4 journals. Those papers have been cited 261 times in total.

Supporting evidence — 4 representative gaps

• Lean Metabolic-Dysfunction-Associated Steatotic Liver Disease (MASLD): Pathophysiology, Diagnostic Challenges, Clinical Outcomes, and Management (2026) · Diseases · doi

  Several priorities for future research and clinical practice can be identified based on current evidence. First, large prospective cohort studies with standardized definitions of lean MASLD are needed to clarify incidence, prevalence, and temporal trends across diverse populations. Harmonization of BMI thresholds, metabolic criteria, alcohol thresholds, and steatosis detection methods will facilitate cross-study comparisons. https://doi.org/10.3390/diseases14050173 Diseases 2026, 14, 173 20 of 25 Second, a deeper understanding of the biological heterogeneity underlying lean MASLD—including genetic, metabolic, microbiome, dietary, sleep-related, and environ- mental contributors—will inform risk stratification and therapeutic targeting. Multi-omics approaches integrating genomics, metabolomics, transcriptomics, and microbiome profiling hold promise. Third, diagnostic tools optimized for lean populations are needed. Existing non- invasive tests were largely developed and validated in broader MASLD or NAFLD cohorts, and lean-specific thresholds for CAP, liver stiffness, ELF, and composite scores require further study. Fourth, lean patients should be intentionally included in clinical trials of MASH pharmacotherapies. Both resmetirom and semaglutide have changed MASH management, but efficacy and safety data in lean patients remain limited [14,16]. Dedicated studies or prespecified subgroup analyses should evaluate treatment response by BMI, waist circumference, visceral adiposity, sarcopenia, diabetes status, and genetic risk. Finally, public health initiatives should emphasize that normal BMI does not exclude clinically important steatotic liver disease. Educational programs and clinical decision support tools should encourage fibrosis risk assessment in lean individuals with hepatic steatosis, metabolic risk factors, or unexplained liver test abnormalities.

  generalfuture workevidence 5/5
  Keywords: lean risk clinical masld thresholds metabolic liver needed populations steatosis diseases genetic microbiome tools patients
• EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) (2024) · Obesity Facts · cited 258× · doi

  (cid:129) In the general population, non-pharmacological mea- sures should be recommended to prevent the devel- opment of MASLD and its complications, including hepatocellular carcinoma, and preventive measures should be reinforced in high-risk groups (LoE 3, strong recommendation, strong consensus). As outlined above, obesity and T2D are strong risk factors for the development and progression of MASLD and are associated with liver-related outcomes including HCC. In addition, an unhealthy diet and a sedentary lifestyle increase the risk of MASLD. Therefore, there is substantial potential to prevent MASLD through lifestyle interventions. Observational prospective studies show an inverse association of MASLD development with the EASL-EASD-EASO Guidelines on the

  generalrecommendationsevidence 5/5
  Keywords: masld risk strong prevent including development lifestyle general population pharmacological sures recommended devel opment complications
• Beyond BMI: Personalized Nutrition in Obesity, Normal-Weight Obesity, Metabolic Syndrome, and MASLD (2026) · Nutrients · doi

  Future research should focus on validating clinically useful biomarkers, harmonizing phenotyping and multi-omics methodologies, evaluating cost-effectiveness, and conducting adequately powered randomized controlled trials to determine which personalized nutrition strategies provide meaningful clinical benefits for specific patient populations. The predictive value of many genetic and microbiome-based biomarkers remains modest, standardized analytical methodologies are lacking, and evidence from large, long-term randomized controlled trials—particularly in patients with MASLD—is still limited.

  generalconclusionsevidence 5/5
  Keywords: biomarkers methodologies randomized controlled trials future focus validating clinically useful harmonizing phenotyping multi omics evaluating
• Metabolic dysfunction associated steatotic liver disease, cardiometabolic multimorbidity and mortality: evidence from the UK biobank (2026) · Clinical Research in Cardiology · cited 3× · doi

  the generalizability of our findings is limited by the characteristics of the UK Biobank, which has a low response rate (5.5%) and predominantly Caucasian participants, - the observational design limits causal interpretation, - MASLD status was assessed only at baseline, and changes during follow-up were not captured, - residual confounding including diet, physical activity, medication adherence, and genetic background may still influence our findings, - the definition of MASLD based on FLI, though practical for large-scale studies, carries a risk of misclassification

  generallimitations sectionevidence 5/5
  Keywords: generalizability findings limited characteristics biobank has low response

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