Abstract / Summary
Abstract Introduction The 2023 nomenclature for metabolic dysfunction–associated steatotic liver disease (MASLD) introduced positive diagnostic criteria but requires only one of five heterogeneous cardiometabolic features, and it does not require direct evidence of insulin resistance, a central pathogenic mechanism of hepatic steatosis. A classification anchored on IR may be more biologically coherent and clinically applicable. Objective To propose Hepatic Insulin Resistance Syndrome (HIRS) as an IR-based framework for diagnosing and staging steatotic liver disease, and to define a strategy for its validation. Methods We developed the framework through narrative synthesis of pathophysiological evidence linking IR to hepatic steatosis, the structure of current MASLD criteria, and published NHANES, UK Biobank, and GSE130970 analyses. We chose elements for measurability and low cost, including use without insulin assays. Validation in NHANES and the UK Biobank is planned and will assess concordance with MASLD, reclassification, and prognostic discrimination, with safeguards against circularity. Results This is a conceptual proposal; we report no original empirical results. HIRS requires hepatic steatosis (elastography-based CAP, imaging, validated serum indices, or histology) plus IR (HOMA-IR, triglyceride-glucose index, or a validated surrogate), with adipose-related dysfunction (waist circumference, triglyceride/HDL ratio, uric acid) as a specifier. Significant alcohol intake, other chronic liver diseases, and steatogenic drugs are excluded. Staging comprises metabolic (HIRS 1), inflammatory (HIRS 2), and fibrogenic (HIRS 3) stages, defined by biochemical activity and liver stiffness. Thresholds are provisional pending derivation and validation. Conclusion HIRS offers an IR-centered alternative to MASLD with explicit, measurable criteria. Replacing MASLD requires empirical validation and expert consensus.