A Context-Informed Framework for Interpreting Iron Status in Heterogeneous Settings: Insights from Peru

Iron deficiency (ID), with or without anemia, remains a major global public health challenge, particularly in populations exposed to inflammatory conditions. Accurate assessment of iron status is difficult because ferritin, the primary biomarker of iron stores, is also an acute-phase reactant that increases during inflammation, potentially masking underlying ID and leading to diagnostic misclassification. The Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) approach uses regression-based methods incorporating C-reactive protein (CRP) and α1-acid glycoprotein (AGP) to adjust iron biomarkers for inflammation. However, its performance in settings characterized by chronic low-grade inflammation, obesity, altitude-related physiology, and environmental stressors remains insufficiently characterized. We propose a context-informed conceptual framework that complements established BRINDA adjustment by considering chronic low-grade inflammation, candidate composite inflammatory markers, and contextual modifiers that may influence the interpretation of iron status. This framework incorporates established and candidate biomarkers, including CRP, AGP, the systemic immune-inflammation index (SII), and the neutrophil-to-lymphocyte ratio (NLR), together with contextual factors such as altitude, metabolic status, and environmental exposures. We also discuss the complex interplay between inflammation and iron metabolism through hepcidin dysregulation and oxidative stress, which may complicate the interpretation of ferritin and other iron biomarkers. Using Peru as an illustrative setting of heterogeneous epidemiological and environmental conditions, we describe how coastal, high-altitude, and Amazonian populations may be differentially affected by these interactions. This context-informed framework provides a structured basis for investigating whether chronic inflammatory and contextual factors add interpretative value beyond established approaches. Prospective and external validation across diverse populations will be required before clinical or public health implementation.