Regulation of haemoglobin concentration at high altitude

Lowlanders sojourning for more than 1 day at high altitude (HA) experience a reduction in plasma volume (PV) that increases haemoglobin concentration and thus restores arterial oxygen content. If the sojourn extends over weeks, an expansion of total red cell volume (RCV) occurs and contributes to the haemoconcentration. While the reduction in PV was classically attributed to an increased diuretic fluid loss, recent studies support fluid redistribution, rather than loss, as the underlying mechanism. The fluid redistribution is presumably driven by a disappearance of proteins from the circulation and the resulting reduction in oncotic pressure exerted by the plasma, although the fate of the disappearing proteins remains unclear. The RCV expansion is the result of an accelerated erythropoietic activity secondary to enhanced renal erythropoietin release, but a contribution of other mechanisms cannot be excluded. After return from HA, intravascular volumes return to normal values and the normalisation of RCV might involve selective destruction of newly formed erythrocytes, although this explanation has been strongly challenged by recent studies. In contrast to acclimatised lowlanders, native highlanders originating from the Tibetan and the Ethiopian plateaus present with a normal or only mildly elevated haemoglobin concentration. Genetic adaptations blunting the erythropoietic response to HA exposure have been proposed as an explanation for the absence of more pronounced haemoconcentration in these populations, but new evidence also supports a contribution of a larger than expected PV. The functional significance of the relatively low haemoglobin concentration in Tibetan and Ethiopian highlanders is incompletely understood and warrants further investigation.image Abstract figure legend Changes in intravascular volumes and haematocrit at high altitude are illustrated along with the principal underlying mechanisms. The red phase in the centrifuged blood samples represents total red cell volume (RCV) and the yellow phase plasma volume (PV). Within 24 h after ascent from low (A) to high altitude, a reduction in PV occurs that increases haematocrit and decreases blood volume (B). The reduction in PV reflects fluid shifts from the intra- to the extra-vascular compartment, rather than diuretic fluid loss. After weeks at high altitude, an expansion of RCV further increases haematocrit and partially restores blood volume (C). The RCV expansion occurs in response to increased renal erythropoietin (EPO) release governed by activation of the local hypoxia-inducible factor-2 (HIF-2) system. After return to low altitude RCV normalizes within 1-2 weeks (D). This normalisation presumably reflects attenuated erythropoiesis due to reduced circulating EPO, rather than accelerated lysis of circulating erythrocytes.image