Plasma Iron Infection Risk: Role of TSAT and HFE C282Y in Immune Defense Original paper

What was reviewed?

This commentary by Drakesmith and Zoller provides an expert synthesis of recent findings linking plasma iron status, hemochromatosis genotypes, and infection risk, with a particular focus on a large Danish cohort study by Mottelson et al. The paper critically reviews evidence that both hypoferremia (low plasma iron) and hyperferremia (high plasma iron), as well as homozygosity for the hemochromatosis-associated HFE C282Y mutation, are independently associated with increased risk of infections. The review places these findings in the context of iron metabolism, genetic determinants of iron homeostasis, and their effects on immune function. It also discusses the nuances of iron compartmentalization, particularly emphasizing the role of transferrin saturation (TSAT) as a key risk marker rather than total body iron stores. The review further explores the implications of these associations for clinical management and emerging therapeutic strategies, and highlights gaps in understanding the mechanistic links between iron status, immune competence, and susceptibility to specific pathogens.

Who was reviewed?

The commentary draws upon data from a variety of populations, but most prominently from a cohort of over 140,000 Danish individuals analyzed by Mottelson et al., which included genetic, biochemical, and clinical outcome data. Among these, a significant subgroup consisted of individuals homozygous for the HFE p.Cys282Tyr mutation, the primary genetic cause of hereditary hemochromatosis in European populations. The review also references findings from the UK Biobank, which includes middle-aged and older adults, and other population-based and genetic studies relevant to iron metabolism and infection risk. The referenced studies collectively span diverse patient groups, including those with iron deficiency, iron overload (hemochromatosis), and the general population, as well as some subgroups with comorbidities such as liver disease, diabetes, or heart failure.

Most important findings

The review highlights a U-shaped relationship between plasma iron status and infection risk, wherein both low and high TSAT are associated with increased susceptibility to infections, particularly pneumonia, sepsis, and skin infections. Notably, the infection risk is more closely linked to plasma iron (as measured by TSAT) than to ferritin (reflecting total body iron stores), suggesting that the circulating iron pool is most relevant for pathogen proliferation and immune function. Homozygosity for HFE p.Cys282Tyr is shown to increase infection risk, even in the absence of overt iron overload or comorbidities, indicating a primary effect of iron dysregulation rather than simply iron excess. The commentary also notes that high TSAT (>45–50%) is associated with adverse outcomes and that iron parameters remain relatively stable over time in most individuals, consistent with a strong genetic influence. Importantly, both impaired iron delivery to immune cells (in deficiency) and increased iron availability to pathogens (in overload) can disrupt host-pathogen balance. Emerging data suggest that the control of plasma iron fluxes—rather than static iron levels—is critical for maintaining immune competence and preventing infections.

Key implications

Clinically, these findings underscore the importance of maintaining plasma iron homeostasis within a normal range to minimize infection risk. For patients with hemochromatosis, this supports a shift in management focus from simply reducing iron stores to actively regulating TSAT—potentially through new therapies such as hepcidin mimetics or gene editing. Conversely, correcting iron deficiency is necessary not only to prevent anemia but also to support immune defense. The review also emphasizes the need for further research to clarify the immunological consequences of low TSAT, including which immune pathways are affected and which pathogens are most relevant. More broadly, the commentary advocates for a paradigm shift in the classification and management of iron disorders, highlighting the centrality of hepcidin deficiency and plasma iron dysregulation rather than just iron overload per se. Given the microbiome’s reliance on host iron availability, these findings have direct implications for understanding microbial signature shifts in iron-related conditions and designing interventions that balance host defense with microbiome stability.

Citation

Drakesmith H, Zoller H. The iron curve: infection at both ends. Comment on Mottelson et al, page 693. Blood. 2024;144(7):679-680. https://doi.org/10.1182/blood.2024025259