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Chapter 68 The Polycythemias 1077

of Andean natives and has been ascribed to desensitization of the Chronic mountain sickness (CMS) is a pathological loss of adap-
carotid bodies to the hypoxic stimulus. The erythrocytosis observed tation to altitude. CMS is a clinical syndrome that occurs in native
in individuals who reside at high altitudes for relatively short periods or lifelong residents living above 2500 m. Anecdotal reports of fami-
of time (days) can also be attributed in part to excessive water loss lies or people being particularly susceptible to CMS are frequently
and contraction of the plasma volume. Total acclimatization of an cited as evidence that certain individuals have an innate susceptibility
individual who moves from sea level to a high altitude may actually to develop CMS. It is characterized by excessive erythrocytosis
require years. Individuals who reside at sea level and are acutely (females, Hb >19 g/dL; males, Hb >21 g/dL); severe hypoxemia; and
exposed to high altitudes are at increased risks of developing deep in some cases, moderate or severe pulmonary hypertension that may
venous thrombosis, pulmonary infarction, retinal hemorrhage, and lead to the development of cor pulmonale and congestive heart
ischemic digits because of increased blood viscosity. High-altitude failure. The clinical picture of CMS gradually disappears after
climbers frequently combat these problems by intravenous adminis- descending to lower altitudes and reappears after returning to high
tration of isotonic saline, with considerable success. altitudes. The prevalence of CMS is higher in men than women and
The chronic responses of various ethnic and racial groups to increases with altitude, aging, associated lung disease, history of
high altitudes are quite variable. Andean natives, known as the smoking, and air pollution. CMS is a public health problem in
Quechua and Ayamara Indians, experience a gradual increase in mountainous regions of the world living above 2500 m. In China
their hemoglobin levels with age. In addition, hemoglobin values are alone, 80 million people live above that altitude, but in South
almost 10% higher in those living at 5500 m above sea level than America, 35 million people live above 2500 m. The CMS phenotype
in those living at 4355 m above sea level. Curiously, their Tibetan has been associated with a single-nucleotide polymorphism (SNP) in
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and Ethiopian counterparts living at similar altitudes do not respond the Sentrin-specific Protease 1 (SENP1) gene. The SENP1 gene
to the resultant chronic hypoxia by increasing their hematocrits. It encodes for a protease that regulates the function of hypoxia-relevant
has been suggested that high levels of nitrous oxide in the exhaled transcription factors such as HIF and GATA, and thus might have
breath of Tibetans may improve oxygen delivery by inducing an erythropoietic regulatory role in CMS through modulation of the
vasodilatation and increasing blood flow to tissues, thus making expression of EPO or EPOR. Fibroblasts obtained from CMS
the compensatory increased RBC volume unnecessary. Interestingly, patients express less SNEP1 protein than their healthy counterparts
Tibetans and Ethiopians have lived much longer as mountain dwell- under hypoxic conditions. SENP1 has been shown to regulate EPO
ers than the Quechua or Ayamara Indians, suggesting that extreme production by regulating the stability of HIF1α during hypoxia, and
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elevation of the RBC mass is a maladaptation that Tibetans and indeed SENP1 mice die of anemia during early life. SENP1 also
Ethiopians have avoided by adopting more physiologic compensa- mediates a positive-feedback loop under hypoxic conditions that is
tory mechanisms. Many residents of the Tibetan plateau reside at responsible for VEGF production and angiogenesis. The major
elevations exceeding 4000 m and experience oxygen concentrations mechanism underlying the development of CMS is relative alveolar
that are about 40% lower than experienced at sea level. Human hypoventilation. Healthy highlanders characteristically hyperventi-
adaptation to a high-altitude environment has been believed to be late. A gradual decline in the rate of alveolar ventilation in these
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the result of advantageous genetic mutations and selective pressure. individuals leads to progressive loss of adaptation to chronic hypoxia
These genetic adaptations are shared by common ancestors within and the development of CMS. The main components of this syn-
East Asian but not Central and South Asian populations and confer drome include (1) alveolar hypoventilation leading to relative
characteristics including adaptation to hypoxia, the absence of CMS, hypercapnia and increasing hypoxemia; (2) excessive polycythemia
and high offspring survival rates. Polymorphisms in the EPAS1 gene leading to increased blood viscosity and expansion of the total lung
that encodes HIF-2α, and the EGLN1 gene, which encodes PHD2, blood volume; (3) pulmonary hypertension and right ventricular
have been positively selected and have been shown to be associated hypertrophy that may evolve to hypoxic cor pulmonale and heart
with the key adaptive features in Tibetans. The putative advantageous failure; and (4) neuropsychiatric symptoms, including sleep disorders,
haplotypes of EGLN1 and EPAS1 have revealed negative correlations headache, dizziness, and mental fatigue. Physical examination reveals
with hemoglobin levels in Tibetans compared with lowlander Han cyanosis of the nail beds, ears, and lips in contrast to the ruddy color
Chinese. Tibetans do not exhibit increased hemoglobin levels at that is characteristic of a healthy highlander. In some cases, the face
high altitude. A high-frequency missense mutation in the EGLN1 is almost black, and the mucosa and conjunctiva are dark red. The
gene, which encodes PHD2, contributes to this adaptive response. fingers are frequently clubbed, and auscultation of the heart reveals
A variant in EGLN1, c.[12C>G; 380G>C], has been shown to con- an increased pulmonary second sound. The patients are frequently
tribute functionally to the Tibetan high-altitude phenotype. PHD2 hypertensive and have evidence of heart failure. Chest radiographic
triggers the degradation of hypoxia-inducible factors (HIFs). The and electrocardiographic findings are characteristic of right atrial and
PHD2 p.[Asp4Glu; Cys127Ser] variant exhibits a lower Km value for right ventricular hypertrophy. Criteria for the diagnosis of CMS have
oxygen, suggesting that it promotes increased HIF degradation under been published and are useful in identifying CMS patients as well as
hypoxic conditions. Whereas hypoxia stimulates the proliferation of monitoring their response to treatment.
WT erythroid progenitors, the proliferation of progenitors with the The definitive treatment for CMS is descent to lower altitudes or
c.[12C>G; 380G>C] mutation in EGLN1 is significantly impaired sea level. The degree of polycythemia decreases after a few weeks or
under hypoxic culture conditions. The c.[12C>G; 380G>C] muta- months, and eventually the hematocrit level returns to sea-level
tion abrogates hypoxia-induced and HIF-mediated augmentation values. Pulmonary hypertension and right ventricular hypertrophy
of erythropoiesis, which provides a molecular mechanism for the gradually resolve and disappear after 1–2 years of living at sea level.
observed protection of Tibetans from polycythemia at high altitude. Phlebotomy or isovolemic hemodilution can reduce the excessive
This individual variability of elevation of serum EPO levels in erythrocytosis and hyperviscosity, improve oxygenation and leads to
high-altitude dwellers and the resultant increase in RBC mass appears relief from symptoms. Due to its transient effects, phlebotomy is not
widespread. For example, acclimatization to moderately high altitudes a long-term treatment for CMS. A variety of drugs has also been
when combined with low-altitude training (so-called living high, evaluated for the treatment of patients with CMS. Ten weeks of the
training low) improves sea-level performance in endurance athletes, respiratory stimulant medroxyprogesterone acetate at doses of 60 mg/
in part because of the erythropoietic effects of altitude exposure. This day led to a reduction of the hematocrit level from 60% to 52% and
substantial individual variability in response to all forms of altitude an increase in arterial oxygen saturation from 84% to 90% in 17
training correlates with improved athletic performance and with eleva- highlanders with CMS. Medroxyprogesterone use, however, was
tion of EPO levels. A large component of this individual variability associated with a loss of libido in men and therefore is infrequently
appears to be related to differences in the peak and rate of decay of used in this population. Therapy with almitrine, a respiratory stimu-
the increase in EPO in response to altitude exposure. These observa- lant, or enalapril, an ACE inhibitor (10 mg/day for 30 days), has
tions suggest that genetically determined variables account for indi- resulted in even more modest reductions of hematocrit levels. Therapy
vidual responses to hypoxia. with acetazolamide is the most useful treatment for CMS.