Abstract
Excessive erythrocytosis (EE) is the hallmark of chronic mountain sickness (CMS), a prevalent syndrome in high-altitude Andean populations. Although hypoxemia represents its underlying stimulus, why some individuals develop EE despite having altitude-normal blood erythropoietin (Epo) concentration is still unclear. A soluble form of the Epo receptor (sEpoR) has been identified in human blood and competes directly for Epo with its membrane counterpart (mEpoR). Thus, reduced levels of circulating sEpoR could lead to higher Epo availability and ultimately to EE. We characterized the relationship between Epo and sEpoR, with hematocrit and hemoglobin concentration in healthy highlanders and CMS patients at 4,340 m in Cerro de Pasco, Peru. Our results show that EE patients show decreased plasma sEpoR levels and can be subdivided into two subgroups of normal and high plasma Epo concentration for the altitude of residence, with hemoglobin concentration rising exponentially with an increasing Epo-to-sEpoR ratio (Epo/sEpoR). Also, we showed that the latter varies as an inverse exponential function of arterial pulse O2 saturation. Our findings suggests that EE is strongly associated with higher Epo/sEpoR values, leading to elevated plasma Epo availability to bind mEpoR, and thereby a stronger stimulus for augmented erythropoiesis. Differences in the altitude normal and high Epo CMS patients with a progressively higher Epo/sEpoR supports the hypothesis of the existence of two genetically different subgroups suffering from EE and possibly different degrees of adaptation to chronic high-altitude hypoxia.
Highlights
EXCESSIVE ERYTHROCYTOSIS (EE; Hb concentration Ն 21 g/dl) is the main sign of chronic mountain sickness (CMS), a clinical syndrome associated with severe hypoxemia and neurological symptoms, such as headache, fatigue, somnolence, and alterations of sleep and memory [27, 36, 38]
Plasma Epo concentration was higher in the high-Epo CMS group than in both normal-Epo CMS and healthy highlander groups (87.1 vs. 43.5 and 37.8 pg/ml, P Ͻ 0.05), while no significant difference was found between these last two (Fig. 1A). soluble form of EpoR (sEpoR) concentration was 16% lower in the normal-Epo CMS and high-Epo CMS groups compared with the healthy group (2.48 and 2.46 vs. 2.86 ng/ml, P Ͻ 0.05; Fig. 1B). sEpoR concentration values were within the range published in previous studies [9, 46]
This observation follows a straightforward rationale, given that Hct and Hb concentration depend on blood Epo, and the latter depends on SaO2 [16]
Summary
EXCESSIVE ERYTHROCYTOSIS (EE; Hb concentration Ն 21 g/dl) is the main sign of chronic mountain sickness (CMS), a clinical syndrome associated with severe hypoxemia and neurological symptoms, such as headache, fatigue, somnolence, and alterations of sleep and memory [27, 36, 38]. There is controversy whether CMS patients have elevated circulating Epo concentration, as some studies have found similar serum Epo values in these individuals compared with healthy highlanders [15, 30], whereas others have not [41]. These findings reflect great variability in blood Epo values at altitude and support the idea of two subgroups of highlanders with EE: one with normal Epo concentration for the altitude of residence, and the other with significantly higher Epo values [12, 30]. Why some individuals develop EE, despite having similar SaO2 and/or blood Epo concentration, is still unclear
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