Iron, altitude, and heart failure: unraveling the hidden links in iron metabolism and hypoxia adaptation

Abstract

Iron deficiency is a critical comorbidity in heart failure that exacerbates symptoms and reduces patients functional capacity. The relationship between iron metabolism and cardiovascular health has been extensively studied, gaps regarding the impact of altitude, on iron homeostasis which may alter iron requirements, storage, and mobilization is unclear.

Current reference values for iron biomarkers, particularly ferritin, transferrin saturation, remain valid across different altitude levels. This systematic review aim to address following questions: How does altitude influence iron metabolism. Do ferritin reference values vary by altitude. What are the clinical implications of altitude-related changes in iron metabolism for the diagnosis and treatment of iron deficiency in HF? The primary objectives of this study are: 1. To systematically assess and synthesize the available evidence on iron supplementation in HF.

A comprehensive and systematic search strategy was employed to identify relevant studies on iron supplementation in heart failure (HF) and the impact of altitude on transferrin saturation, hepcidin levels, and ferritin values. The search was conducted across multiple electronic databases, including PubMed (MEDLINE), Embase, Cochrane Library, Web of Science, and Scopus, The analysis conducted on reference ferritin values adjusted for altitude showed that for every meter of elevation above sea level, ferritin levels increase by 0.0037 ng/mL (95% CI: 0.0037, p < 0.001). This result indicates that ferritin is a biomarker affected by altitude, suggesting the need to adjust clinical cut-off values for populations living at higher elevations. The fixed-effects model has an R² of 1.000, meaning that altitude fully explains the variability in the adjusted ferritin values. the AUC (-355.0) and BIC (-355.4) values indicate that the model has an optimal statistical fit. The heterogeneity analysis shows and I² of 0.00%, confirming that there is no significant variability among the adjusted ferritin values, which is expected since the data were adjusted based on a well-defined linear model. Clinically, this implies that normal ferritin values could be adjusted according to altitude, while at sea level, the standard value is 100 ng/mL, at 3000 meters, the expected value is 111.1 ng/mL, and at 5000 meters, it can reach 118.5 ng/mL. This has implications for diagnosing iron deficiency in high-altitude regions, as using standard reference values could lead to misdiagnoses of iron deficiency in populations that exhibit normal physiological adaptation to hypoxia. From a practical perspective, this studies analysis suggests that the cut-off values for defining iron deficiency in high-altitude populations (≥ 3000 m) likely increased by 10-15 ng/mL to reflect the adaptive physiology and may be particularly relevant in groups such as high-altitude athletes, pregnant women, and HF patients in mountainous regions such as Andes and Tibet.