In this issue of Blood, Staub and colleagues roughly recreate the rugged topographical map of Switzerland by plotting the hemoglobin (Hb) concentrations and residential altitudes of nearly 72 000 male Swiss Army conscripts.1 

The surprise comes from the altitudes surveyed: 200 to 2000 m above sea level (masl), which covers Geneva (374 masl) and Davos (1560 masl) but not the Matterhorn (4487 masl). Blood readers who are aware of the increased Hb concentrations among high-altitude visitors and residents of Andean, European, Han Chinese, and Oromo (Ethiopia) ancestry may wonder why the Swiss findings are newsworthy. Adaptation to hypoxia is usually studied at altitudes of 2500 m or more because “O2 levels in arterial blood do not markedly fall until above ∼8,000 ft (2,300 m).”2(p1371). Staub et al set out to answer the question of whether modest increases in altitude below 2000 masl impact Hb concentration. They do. Evidence summarized in 6 altitude bands of 300 m each shows that Hb concentration rose from a mean of 155.2 g/L at altitudes <300 masl to 159.6 g/L at altitudes ≥2000 masl. The rise implies that our cells sense and respond to graded changes in ambient hypoxia across the entire attainable range of altitudes from sea level to Mount Everest, even in the absence of marked changes in oxygen levels in arterial blood at the lower altitudes. The very large and homogeneous sample of young Swiss men enabled the detection of the subtle difference of just +2.8% in Hb concentration that might not be discovered by smaller clinical or field studies.

Hypoxia inducible factors (HIFs) regulate graded responses to fluctuations in cellular oxygen levels. HIFs induce the transcription of EPO and other loci that contribute to Hb synthesis, consistent with the report by Staub et al that associates lower amb2ient oxygen levels with higher Hb concentrations.3  The HIFs negatively regulate the iron storage protein ferritin; however, Staub et al report an increase in ferritin levels with altitudes up to 1200 to 1499 masl. They hypothesize the existence of mechanisms to increase iron stores under chronic mild hypoxia, perhaps by modifying iron absorption and release by the gut. Interestingly, a different study of young men chronically exposed to 2210 masl reported higher Hb concentration and ferritin compared with sea-level controls.4  Investigating HIF and non-HIF oxygen sensing systems5  could be informative in these settings.

The findings of Staub et al speak to the ongoing initiative by the World Health Organization (WHO) to revise its recommendations for detecting anemia using Hb concentration thresholds.6,7  The WHO guidelines advise applying an altitude correction to increase the Hb concentration threshold for diagnosing anemia. Studies of Andean men provided scientific justification. We now know that Tibetan and Amhara (Ethiopia) highlanders have dampened Hb concentration responses to altitude.8  Consequently, WHO thresholds vastly overestimate anemia in healthy, iron-sufficient Amhara highlanders and Andean women.9,10  WHO revisions should take into account population differences in adaptation to high-altitude hypoxia. Another recommendation to WHO, prompted by the findings of Staub et al, proposes that altitude corrections to Hb concentration thresholds begin at 250 masl rather than the current 1000 masl. Taking into account population differences in response to hypoxia, the full range of residential altitudes and their interactions could complicate WHO’s task of revising its guidelines.

In conclusion, the article by Staub et al speaks to basic science questions by providing evidence that healthy young men sense and respond systemically to changes in ambient oxygen levels occurring as low as 300 masl and that an unknown mechanism may increase iron stores at similarly low altitudes. Patients with illnesses that cause mild hypoxemia may benefit from new research on HIF and non-HIF responses to subtle changes in oxygen availability that may help or hinder recovery. The Swiss Army conscripts who provided the data enabled insights into the important public health question of how to diagnose anemia. Replication studies in this population and others with different patterns of response to high-altitude hypoxia should follow.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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