High‐altitude adaptation: where Tibetans and Han Chinese agree

In this issue of Experimental Physiology, Simonson et al. (2014) report on an elegant study showing that adapted Tibetans and acclimatized Han Chinese at the altitude of 4200 m present with a leftward shift of the oxyhaemoglobin (HbO2) dissociation curve. The authors defined the position of the HbO2 dissociation curve by the measurement of P50, which is the PO2 at 50% oxygen saturation of haemoglobin. The normal value of P50 is about 27–28 mmHg when pH is 7.4, the PCO2 40 mmHg and the temperature 37°C (‘standard P50’). Reporting P50 as in vitro ‘standard P50’ is of obvious importance to differentiate intrinsic changes in the affinity of haemoglobin for oxygen from those resulting from in vivo changes in pH, PCO2 or body temperature. A rightward shift of the HbO2 dissociation curve is identified by an increased P50, and a leftward shift by a decreased P50. Patients with a decreased oxygen-carrying capacity of the cardiovascular system, such as in anaemia or hypoxaemic cardiac or pulmonary diseases, present with a rightward shift of the oxyhaemoglobin dissociation curve. This favours the unloading of oxygen, thus helping to prevent tissue deprivation of oxygen. The same is observed in conditions of hypobaric hypoxia, in lowlanders acclimatized to high altitudes and in people born and permanently living at high altitudes on the South-American altiplano. In all these situations, the P50 is increased. On the contrary, high-altitude vertebrate species, such as the llama or the bar-headed goose, present with a decreased P50. This is advantageous at altitudes >4000 m, where alveolar PO2 is lower than 50–60 mmHg and the plateau portion of the oxyhaemoglobin dissociation curve disappears, so that an increased affinity of haemoglobin for oxygen is associated with an increased alveolocapillary transfer of O2, resulting in higher oxygen content of the blood. A decreased P50 is arguably a better adaptative scenario, allowing for increased O2 delivery with less polycythaemia (West et al. 2013). As proof of this concept, Hebbel et al. (1978) reported on two subjects with a high-oxygen-affinity haemoglobin (Hb Andrew Minneapolis), resulting in a standard P50 of 17 mmHg, compared with a P50 of 27 mmHg in two of their normal siblings. At low altitude, the subjects with low P50 had a lower maximal O2 uptake (V̇O2 max). At high altitude, the subjects with low P50 had a higher V̇O2 max by 10%, while the normal P50 subjects had a lower V̇O2 max by 17%. These results confirmed model predictions. Tibetans adapt to altitude with less polycythaemia than their Andean counterparts, and this has long been thought to be related to a relatively lower P50 even though reported numbers vary greatly (West et al. 2013). Tibetan but not Andean physiology thus resembles that of high-altitude animal species. This may be explained by a longer Darwinian evolution. The colonization of the Peruvian Andes has been taking place over the past 1400 years, while man first inhabited Central Asia, including Tibet, perhaps as early as 30,000 years ago (Aldenderfer, 2011). Simonson et al. (2014) report on a slightly lower P50, by an average of 1.7 mmHg, in Tibetans compared with subjects residing at sea level and argue that these data contrast with the expected increase in P50 that would be of some 6 mmHg. However, curiously, the P50 values they found in acclimatized lowlander Han Chinese were not different from those of the Tibetans. How might this be? There are no previous data suggesting that Han Chinese acclimatize in a different manner from other lowlander ethnic groups. There is thus some uncertainty in the reported measurements. The study groups were rather small and disparate in size, with many variables to compare. Such a design increases the likelihood of false-positive or -negative signals. There is also a concern about the method used for the calculation of P50 from arterial PO2 and pulse oximetry O2 saturation. The authors validated pulse oximetry against co-oximetry, but one would have liked confirmation with gold-standard tonometry. How relevant are the reported P50 measurements? Simonson et al. (2014) found no correlation between V̇O2 max and P50 over a rather wide range of values, from 22 to 31 mmHg. This may not be surprising because aerobic exercise capacity measured as the V̇O2 max at >4000 m has not been found to be different in Sherpas (who are of Tibetan ethnicity), South American Quechua or Aymara or acclimatized European lowlanders (Faoro et al. 2014). This is sometimes referred to as the ‘V̇O2 paradox’ because it contrasts with the popular belief that high-altitude dwellers outperform acclimatized lowlanders (Brutsaert, 2008). A lower P50 may be needed to provide benefit. Research at high altitudes is extraordinary difficult because of the harsh environment, limited local co-operation and reliance on (trans)portable devices, so that small sample sizes and use of surrogate measurements are inevitable. Simonson et al. (2014) are to be commended for their bold attempt to put previous controversies straight, especially in the current context of genetic studies much in need of improved and robust phenotyping. Their paper paves the way for methodologically stronger studies on larger populations living permanently at high altitudes.