Plasma IGFBP7 improves risk reclassification for liver-related outcomes: insights from proteo-transcriptomic profiling

Background & Aims
Advanced liver fibrosis is a pivotal predictor of liver-related outcomes (LROs), yet existing non-invasive tests offer limited prognostic accuracy. We aimed to identify novel plasma protein biomarkers that enhance long-term risk stratification for LROs.
Methods
Proteomic analyses were first conducted in 191 MASLD patients, including 79 with advanced fibrosis and 112 with mild fibrosis, to identify differential plasma proteins. These proteomic findings were then integrated with liver transcriptional profiling from 206 MASLD patients, comprising 68 with advanced fibrosis and 138 with mild fibrosis, to determine candidate biomarkers. The prognostic utility of these biomarkers was validated in 42,979 participants from the UK Biobank with a median follow-up of 13 years. Discriminatory performance and cumulative incidence were assessed using competing-risk methodologies.
Results
Proteo-transcriptomic integration identified 123 concordant candidates, among which four plasma proteins (ADAMTSL2, IGFBP7, MFAP4, and CLSTN2) demonstrated robust diagnostic performance for advanced fibrosis (AUCs 0.821–0.889). In the UK Biobank cohort, IGFBP7 emerged as the strongest predictor of LROs, outperforming FIB-4, APRI, and CLivDlab, with time-dependent AUCs of 0.815, 0.773, and 0.761 for cirrhosis prediction at 5, 10, and 15 years, respectively. Elevated IGFBP7 levels were detectable up to 15 years prior to diagnosis and, when combined with CLivDlab, identified a high-risk subgroup with a 20% 15-year incidence of cirrhosis. Subgroup analyses showed consistent prognostic value across metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated alcohol-related liver disease, and alcohol-related liver disease, with particularly strong performance in MASLD (15-year AUCs > 0.85).
Conclusions
Plasma IGFBP7 is a robust and independent predictor of liver-related outcomes and significantly enhances risk stratification beyond conventional clinical tools.
Impact and implications
This study demonstrates that IGFBP7 is both a biomarker of advanced liver fibrosis and a strong long-term predictor of liver-related outcomes. The integration of IGFBP7 with conventional non-invasive tests enhances the refinement of risk prediction. Among individuals with low CLivD scores, those with high IGFBP7 levels had a substantially increased incidence of liver-related outcomes (2.5%), while low IGFBP7 levels were associated with favorable outcomes even in high CLivD groups (0.8%). This enables more precise identification of patients who may benefit from early referral versus those suitable for reduced monitoring, potentially optimizing care pathways in resource-limited settings. Moreover, IGFBP7 demonstrated consistent applicability across all categories of steatotic liver disease defined by the current Delphi consensus framework, underscoring its broad clinical utility.