A Population-based and Clinical Cohort Validation of the Novel Consensus Definition of Metabolic Hyperferritinemia

Background: There is limited data on the clinical significance of metabolic hyperferritinemia (MHF) based on the most recent consensus. We aimed to validate the clinical outcomes of MHF in general population and biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD) patients. Methods: NHANES database and PERSONS cohort were included. MHF was defined as elevated serum ferritin with metabolic dysfunction (MD) and stratified into different grades according to ferritin (grade 1: 200 [females]/300 [males] - 550 ng/ml; grade 2: 550 - 1000 ng/ml; grade 3: > 1000 ng/ml). The clinical outcomes, including all-cause death, comorbidities and liver histology were compared between non-MHF and MHF in adjusted models. Results: In NHANES, compared with non-MHF with MD, MHF was related to higher risks of advanced fibrosis (FIB-4, P = 0.036), elevated albumin-creatinine ratio (UACR, P = 0.001) and sarcopenia (P = 0.013). Although the association between all grades of MHF and mortality was insignificant (P = 0.122), grades 2/3 was associated with increased mortality (P = 0.029). While comparing with non-MHF without MD, the harmful effects of MHF were more significant in mortality (P < 0.001), elevated UACR (P < 0.001), cardiovascular disease (P = 0.028), and sarcopenia (P < 0.001). In PERSONS cohort, MHF was associated with more advanced grades of steatosis (P < 0.001), lobular inflammation (P < 0.001), advanced fibrosis (P = 0.017), and more severe hepatocellular iron deposition (P < 0.001). Conclusions: Both in general population and at-risk individuals with MAFLD, MHF was related with poorer clinical outcomes.