Clinical bottom line
Serum hepcidin measurement is a promising, yet still investigational, biomarker for assessing iron overload in chronic liver diseases (CLD). It reflects iron regulatory status and inflammatory signals influencing iron metabolism. Current evidence suggests hepcidin levels correlate variably with iron burden and disease activity across CLD etiologies, including nonalcoholic fatty liver disease (NAFLD) and dysmetabolic iron overload syndrome (DIOS). However, heterogeneity in assay methods, patient populations, and confounding inflammation limit its routine clinical use. Hepcidin may complement traditional iron indices and imaging but requires further validation before widespread adoption for diagnosis or management guidance in iron overload states associated with CLD.
What the evidence shows
Hepcidin, a liver-produced peptide hormone, is the master regulator of systemic iron homeostasis by controlling intestinal absorption and macrophage iron release. In chronic liver diseases, iron overload is common and contributes to disease progression and complications. Traditional markers such as serum ferritin and transferrin saturation are influenced by inflammation and liver dysfunction, complicating iron status assessment.
Penkova et al. (2013) measured serum hepcidin in patients with various CLDs and found significantly altered hepcidin levels compared to controls, with lower levels in iron-deficient states and higher levels in inflammatory or fibrotic liver disease, suggesting hepcidin reflects both iron status and hepatic inflammation. Similarly, Trombini et al. (2011) demonstrated that patients with DIOS exhibit an impaired hepcidin response to iron loading, indicating dysregulated iron metabolism distinct from hereditary hemochromatosis.
Boga et al. (2015) studied NAFLD patients and reported that serum hepcidin correlated with hepatic iron overload assessed by biopsy and imaging, but the relationship was modulated by inflammation and metabolic factors. Yu et al. (2025) highlighted the prognostic value of iron metabolic disturbances and inflammatory iron biomarkers, including hepcidin, in liver transplant outcomes, suggesting a potential role in risk stratification.
Ahmed et al. (2024) emphasized the utility of hepcidin combined with total iron-binding capacity in diagnosing iron deficiency in complex clinical scenarios, underscoring its potential as part of a multi-marker panel rather than a standalone test.
Caveats and uncertainty
Despite promising findings, several limitations hinder the clinical application of serum hepcidin measurement in CLD:
- Assay variability: Different hepcidin assays (mass spectrometry vs immunoassays) yield variable results, lacking standardized reference ranges, which complicates interpretation and inter-study comparisons.
- Influence of inflammation: Hepcidin is an acute-phase reactant induced by inflammatory cytokines, making it difficult to distinguish iron overload from inflammation-driven hepcidin elevation in CLD.
- Heterogeneous populations: Studies often include mixed CLD etiologies with variable iron loading patterns, limiting generalizability.
- Cross-sectional data: Most evidence is observational and cross-sectional; longitudinal data on hepcidin dynamics during disease progression or treatment are sparse.
- Limited clinical outcome data: The impact of hepcidin-guided management on patient outcomes remains unproven.
How this may change practice
Serum hepcidin measurement holds potential as an adjunctive biomarker to improve the diagnosis and management of iron overload in chronic liver diseases by:
- Enhancing differentiation between true iron overload and inflammation-related ferritin elevation.
- Informing individualized iron reduction strategies, such as phlebotomy or chelation, particularly in DIOS and NAFLD.
- Potentially serving as a prognostic biomarker in liver transplantation and advanced liver disease.
However, before routine clinical implementation, standardized assays, validated reference ranges, and prospective studies demonstrating clinical utility and outcome benefits are necessary. Clinicians should continue to rely on established iron indices and imaging modalities, considering hepcidin as an investigational tool within research or specialized centers.