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874 Part VI: The Erythrocyte Chapter 57: Primary and Secondary Erythrocytoses 875

(Chap. 49). In chronic acclimatization, blood pH is slightly increased, selection in genomic regions in Tibetans; not surprisingly, most are
and when this is taken into account, the dissociation curve is shifted haplotypes comprising genes that are components of hypoxia sens-
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approximately to normal. It is unlikely that a shift to the right would be ing that are mediated by hypoxia-inducible factors (HIFs) (described
to the advantage of high-altitude dwellers, except as a partial compensa- in Chap. 32). Two of these selected regions include genes that have
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tion for respiratory alkalosis. In addition, a right-shifted curve also has undergone the strongest genetic selection, and are thus likely the most
a decrease in oxygen loading in the alveolar capillary, minimizing any beneficial for Tibetan adaptation. These two regions encompass the
net gain in off-loading. There is a relationship between higher altitude EPAS1 gene, encoding the α subunit of HIF-2, and the EGLN1 gene,
and hemoglobin concentration response, best studied among Andean encoding proline hydroxylase 2 (PHD2). PHD2 is the principal nega-
highlanders and Europeans in the United States; hemoglobin concen- tive regulator of both HIF-1 and HIF-2. Both of these haplotypes were
tration is almost 10 percent higher in those Andean highlanders living shown to be associated with differences in hemoglobin concentration
at 5500 m than in those living at 4355 m. Furthermore, native Andean at high altitude by several independent studies. 74–76 Intriguingly, the
high-altitude dwellers have a gradual increase in their hemoglobin EPAS1 haplotype was previously identified as having the strongest
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levels with age and body weight. Although it has been postulated Tibetan positive selection and was found to have an unusual haplo-
that high hemoglobin–oxygen affinity in the setting of extremely low type structure that originated by introgression of DNA from Deniso-
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ambient oxygen may be one such adaptive change, increased hemo- van or Denisovan-related hominins. Denisovans, a sister group to the
globin–oxygen affinity or increased fetal hemoglobin are not adaptive Neanderthals, branched off from the human lineage perhaps 600,000
phenotypes of Tibetan or Andean highlanders. 63 years ago, and available evidence suggests that Denisovan and Nean-
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In a subset of Andean high-altitude native dwellers, namely Que- derthal hominins contributed to the modern homo sapiens admixture
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chua and Aymara Indians, polycythemia becomes excessive and often before their extinction, likely by interbreeding, and that these hominin
results in chronic mountain sickness with its associated constitutional species provided genetic variations that helped humans adapt to new
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symptoms and pulmonary hypertension. 42,60 This excessive erythrocy- environments, such as extreme hypoxia associated with high altitude.
tosis, called Monge disease or chronic mountain sickness, 42,64 is also The first Tibetan adaptation gene mutation identified, which changes
described in Han Chinese living in Tibet and occurs in whites living the encoded PHD2 protein within the selected haplotype, is a missense
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at high altitudes. 66 variant of the EGLN1 gene, c.12C>G, that is in near complete link-
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The polycythemia encountered in high-altitude dwellers is often age disequilibrium with a previously reported missense variant, EGL-
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considered to be a universal, uniform adaptation process to hypoxia N1:c.380G>C. Both EGLN1:c.[12C>G; 380G>C] (PHD2 D4E,C127S ) are in
that would arise in all normal individuals. In reality, there is marked cis; that is, the constituting PHD2 D4E,C127S locus. Analysis of Tibetans and
variability in erythropoietin level and subsequent polycythemic related populations suggests that 12C>G started on the 380G>C variant
response to chronic hypoxia, 60,67 suggesting that some of these factors that is not Tibetan specific, 80,81 that PHD2 D4E,C127S originated from a sin-
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may be genetically determined; the same degree of hypoxia induces gle individual approximately 8000 years ago, and that now greater than
substantial differences in erythropoietin production in response to 80 percent of Tibetans carry this PHD2 variant. Functional assess-
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high altitude. 62,68,69 Three distinct adaptations to high altitude appear to ment of homozygous PHD2 D4E,C127S recombinant proteins showed that
have evolved. Andean highlanders have higher oxygen saturation than the variant protein has increased hydroxylase activity under hypoxic
Tibetans at the same altitudes. Tibetan mean resting ventilation and conditions. Furthermore, native homozygous PHD2 D4E,C127S erythroid
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hypoxic ventilatory response are higher than Andean Aymaras, whereas progenitors have blunted erythropoietic responses to hypoxia by both
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the mean Tibetan hemoglobin concentration is below the Andean erythropoietin-specific and erythropoietin-independent mechanisms.
mean. High levels of nitric oxide (NO) in the exhaled breath of Tibet- Although this is the first identified variant that contributes to the molec-
ans may represent increased physiologic NO. This effect may improve ular and cellular basis of Tibetan adaptation to high altitude, there are
oxygen delivery by inducing vasodilation and increasing blood flow other evolutionarily selected genomic regions, and elucidation of their
to tissues, thus making the compensatory increase in red cell volume functional impact is, at the time of this writing, unknown.
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unnecessary. Another distinct successful pattern of human adaptation Understanding the etiology of polycythemia of high altitude is
in high-altitude dwellers that contrasts with both the Andean “classic” made more complex by a study of inhabitants of the Peruvian mining
(arterial hypoxemia with polycythemia) and Tibetan (arterial hypox- community of Cerro de Pasco (altitude 4280 m) with excessive erythro-
emia with normal venous hemoglobin concentration) patterns evolved cytosis (mean hematocrit: 76 percent; range: 66 to 91 percent). About
in Ethiopia. While Ethiopian high-altitude dwellers have hemoglo- half of those individuals with a hematocrit greater than 75 percent had
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bin concentrations that fall in the normal range (15.9 and 15.0 g/dL toxic serum cobalt levels, suggesting that other erythropoiesis promot-
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for males and females, respectively), they have a surprisingly, as-yet- ing factors such as cobalt can augment hypoxia induction of erythro-
unexplained high (average of 95.3 percent) oxygen saturation of hemo- poietin, causing extreme polycythemias (Chap. 32). Most high-altitude
globin despite their hypoxic environment (reviewed in Ref. 62). Their dwellers do not have measurable levels or a history of exposure to cobalt
cerebral circulation is increased but is insensitive to hypoxia, unlike or other heavy metals. 84
Peruvian high-altitude dwellers. Thus, Ethiopian highlanders maintain
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venous hemoglobin concentrations and arterial oxygen saturation within Erythrocytosis of Pulmonary Disease
the ranges of sea level populations, despite the decrease in ambient oxy- Degrees of arterial hypoxia comparable to those observed in individ-
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gen tension at high altitude. Tibetans and Ethiopians have lived as uals at high altitudes are observed in patients with right-to-left shunt-
mountain dwellers much longer than the Quechua or Aymara Indians, ing resulting from cardiac or intrapulmonary shunts or to ventilation
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suggesting that extreme elevation of red cell mass is a maladaptation that defects, as in COPD.
Tibetans avoided by evolving a more efficient, or less detrimental, com- Many patients with COPD with severe cyanosis are not poly-
pensatory mechanism than that which causes Monge disease. cythemic. This has been attributed to infections and inflammation often
With rapid advances in genomics (Chap. 11), progress has been present in the lungs, resulting in anemia of chronic inflammation, and
made in identification of the molecular basis of high-altitude adapta- to an increase in plasma volume. Why some patients with lung disease
tion; most of these advances have been in our understanding of Tibetan and congenital heart disease develop polycythemia, while others do not,
adaptation. Several studies reported evidence for positive natural is not entirely clear.

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