Current WHO hemoglobin thresholds for altitude and misdiagnosis of anemia among Tibetan highlanders
Authors: Kaylee Sarna, Gary M. Brittenham, Cynthia M. Beall
Journal: American Journal of Hematology (2020)

The World Health Organization (WHO) has begun a 4-year project to review its global guidelines for hemoglobin thresholds used to define anemia at the individual and population levels.1 Current WHO guidelines define anemia as a condition in which the oxygen-carrying capacity of red blood cells is insufficient to meet physiologic needs, and recommend the use of a single table of standard adjustments for altitude.2 Two recent commentaries in the American Journal of Hematology described extensive misdiagnosis of iron-sufficient Andean and East African highlanders as anemic upon applying the current WHO standard adjustments for altitude of residence.3 We now present further evidence of substantial differences in adaptations to hypoxia in distinct populations at altitude and the need for population specific reference values for hemoglobin.4 We describe a healthy, non-smoking, iron-sufficient, not pregnant or recently delivered adult Tibetan sample, whose physiologic needs for oxygen are being met at hemoglobin concentrations that would be defined as anemic, using current WHO altitude adjustments. Details of the sample living at 3932 m in the Tibet Autonomous Region of China are described elsewhere.5 Iron-replete subsamples (plasma ferritin >12 μg/L and erythrocyte zinc protoporphyrin concentrations ≤70 μg/dL) are reported here to assess the prevalence of anemia misdiagnosis. The Tibetan high-altitude residents have hemoglobin concentrations that are roughly 1 g/dL lower than the altitude adjusted WHO thresholds. The Tibetan men have mean hemoglobin concentrations of 15.6 ± 1.5 SD g/dL (n = 72); women have average hemoglobin concentrations of 14.2 ± 1.1 g/dL (n = 52). The Tibetan mean hemoglobin concentrations fall within one SD of the mean for a United States national low-altitude sample.6 Figure 1 shows the hemoglobin distribution of Tibetan men and women after applying the current WHO hemoglobin threshold values adjusted for age and sex (denoted with a solid vertical line) and for age, sex, and altitude (denoted with a dotted vertical line). Accounting for age and sex alone, Tibetan men had an apparent anemia (hemoglobin <13 g/dL) prevalence of 1.4% (one male) and women had no anemia (hemoglobin <12 g/dL). The WHO-recommended altitude adjustment, established using data on Andean highlanders, raised the prevalence of apparent anemia among Tibetan men to 77.8% (<16.5 g/dL) and 86.5% (<15.4 g/dL) among women. The unelevated hemoglobin concentration of Tibetans associate with a variant at the EPAS1 locus that shows signals of natural selection and occurs at high frequency exclusively among Tibetans. Unelevated hemoglobin concentrations are associated with higher exercise capacity and greater reproductive success among Tibetans.7 In summary, evidence from one Asian, two East African and several South American samples residing above 3500 m demonstrates the diversity of physiological responses at altitude and complements recent meta-analyses.4 These data indicate that continued use of a single table of altitude adjustments to the WHO hemoglobin thresholds would result in substantial misdiagnosis of anemia in some populations. New WHO guidelines should take account of quantitatively different physiological adaptations to hypoxia among populations living at altitude by determining population specific thresholds of hemoglobin concentrations for the diagnosis of anemia. The authors thank the Tibet Academy of Social Sciences, Lhasa, Tibet Autonomous Region for hosting the Tibet portion of this field study and the Bolivian Institute of High-Altitude Biology for hosting the Bolivia portion. We are grateful to Ms. Linda Bowman and Ms. Judi Minium for laboratory analyses in Cleveland. The National Science Foundation Award No. 9706980 supported this study.