Coherence Loss in Iron Homeostasis: A Systems Model for HFE Carriers Under Inflammatory Load

This manuscript introduces a systems-medicine framework for understanding iron regulation in individuals heterozygous for HFE gene variants. Hereditary haemochromatosis (HH) is traditionally framed as a binary autosomal-recessive condition, with biallelic HFE mutations conferring risk and heterozygous “carrier” states considered physiologically neutral. However, iron metabolism is now understood as a multi-layer regulatory network involving genetic signals, inflammatory pathways, endocrine factors, and cellular metabolic demand. In this context, binary Mendelian assumptions may not fully capture regulatory behaviour under inflammatory stress. This work proposes that HFE heterozygosity may represent a partial-coherence regulatory state that remains compensated at baseline but may be vulnerable to perturbation during sustained inflammation. Drawing on a coherence-based systems model, the manuscript conceptualises iron homeostasis as a dynamic feedback network linking HFE-mediated iron sensing, hepcidin regulation, ferroportin activity, and cytokine-driven immune signalling. Chronic inflammatory signalling, particularly via IL-6–mediated hepcidin induction, is modelled as a phase-inverting input that can destabilise iron handling in partial-amplitude regulatory states. To operationalise this model for future research, an Iron–Inflammation Incoherence Index (I³) is proposed, integrating standardised hepcidin, transferrin saturation, and C-reactive protein values. This index is not intended as a diagnostic tool, but as a conceptual metric to support hypothesis-driven exploration of iron–immune dynamics. No patient data are presented, and no clinical conclusions are drawn. The manuscript provides a theoretical basis for prospective investigation and aims to stimulate dialogue between haematology, immunology, and systems physiology. The work positions iron regulation not as a binary genetic trait, but as a continuum of regulatory resilience shaped by inflammatory context.