Insulin-like Growth Factor-1 Reflects Liver Disease Stage and Improves Prediction of Liver-related Mortality

• Published in: Clinical gastroenterology and hepatology
• Main Authors: Schneider, Carolin V., Gross, Stefan, Balasubramani, Sriram, Tomanová, Petra, Schrader, Christina, Fromme, Malin, Mandorfer, Mattias, Guldiken, Nurdan, Schneider, Kai Markus, Lurje, Georg, Raptis, Anastasia, Huang, Helen Ye Rim, Mueller, Sebastian, Reiberger, Thomas, Nahon, Pierre, Anstee, Quentin M., Daly, Ann K., Govaere, Olivier, Strnad, Pavel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.05.2025
• Subjects: Gastroenterology and Hepatology; IGF-1; Liver-related Death; Liver-related Outcomes; Mortality; Prediction; ICD-10; MRI; CPS; ALT; AUROC; STROBE; Liver-related Outcomes; scRNAseq; AATD; ANOVA; PLT; BMI; AST; Mortality; CI; Prediction; HVPG; IGF-1; IQR; MASLD; UKB; PheWAS; GGT; APRI; FIB-4; CIRRUS; Liver-related Death; ELISA; LRD; single-cell RNA sequencing; hepatic venous pressure gradient; Child-Pugh score; insulin-like growth factor-1; alpha-1 antitrypsin deficiency; gamma-glutamyl transferase; Phenome-Wide Association Study; body mass index; Fibrosis-4; platelets; CIRRhosis Using Standard tests score; magnetic resonance imaging; interquartile range; analysis of variance; alanine transaminase; AST-to-platelet ratio index; area under the receiver operated characteristic; International Classification of Diseases, 10th Revision; metabolic dysfunction-associated steatotic liver disease; enzyme-linked immunosorbent assay; confidence interval; aspartate transaminase; Strengthening the Reporting of Observational studies in Epidemiology; UK Biobank
• ISSN: 1542-3565; 1542-7714; 1542-7714
• DOI: 10.1016/j.cgh.2025.02.030

Liver-related mortality represents a growing public health concern, disproportionately affecting younger subjects. Because there are no established tools for early detection of individuals at risk for liver-related death (LRD), we analyzed LRD predictors in the UK Biobank (UKB) data and validated the usefulness of serum insulin-like growth factor-1 (IGF-1). The UKB dataset encompassing 325,981 participants, a median follow-up of 13.5 years, and 846 LRDs was used as a training cohort. IGF-1 was validated in several independent cohorts of different liver disease etiologies and fibrosis stages. A Cox proportional hazard model was used to develop the gamma-glutamyl transferase (GGT)-IGF-1 score that was validated in an independent UKB cohort with 83,528 subjects and 237 LRDs. Among 59 variables in the UKB training cohort, GGT and IGF-1 were identified as the LRD predictors with time-dependent area under the curve (AUROC) >80%. Phenome-wide association study demonstrated the higher liver specificity of IGF-1 compared with GGT. In validation cohorts, IGF-1 levels: (1) increased in subjects with alcohol misuse after alcohol detoxification; (2) were reduced in individuals with alcohol-related/steatotic liver disease or severe alpha-1 antitrypsin deficiency and higher fibrosis stages; and (3) were diminished in participants with more advanced liver cirrhosis and lower levels associated with higher mortality. In the UKB training and validation cohorts, the novel GGT-IGF-1 score achieved an AUROC of 0.87 for LRD and was significantly better than established risk scores (AUROC = 0.77–0.81). The study highlights the usefulness of IGF-1 as a reliable predictor of LRD and identifies a novel, population-based screening tool outperforming the currently used scores. [Display omitted]