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Chapter 68 The Polycythemias 1079

suppressor activity of PHD2 has also been reported in sporadic therefore leads to increased affinity of hemoglobin for oxygen, result-
endometrial, breast, and pancreatic cancers, with inactivating muta- ing in a lifelong hypoxic stimulus and erythrocytosis.
tions ultimately leading to the increased production of growth factors Congenital methemoglobinemias, whether caused by cytochrome
that contribute to tumor growth. Two plasma cell dyscrasias, POEMS b5 reductase mutations or globin mutations, may be associated with
(Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal mild polycythemia (see Chapter 43). When hemoglobin is oxidized
protein, Skin changes) syndrome and TEMPI (Telangiectasias, to methemoglobin, all of the four subunits of the tetramer may be
Erythrocytosis with elevated erythropoietin levels, Monoclonal gam- affected, eliminating the oxygen transport capacity of hemoglobin.
mopathy of unknown significance [MGUS], Perinephric fluid col-
lections, and Intrapulmonary shunting syndrome) have been recently
been reported to be associated with erythrocytosis. Treatment is Hypoxia-Inducible Factor Pathway Mutations
directed at the underlying disease. In TEMPI syndrome, the most Leading to Erythrocytosis
effective treatment has been bortezomib, which suggests that TEMPI
syndrome is a consequence of the abnormal plasma cell clone. Alterations of a number of proteins in the HIF pathway have been
shown to lead to increased EPO production and erythrocytosis (see
Fig. 68.1). Chuvash polycythemia (CP) is an autosomal recessive
Polycythemia in Endocrine Disorders disorder associated with germ-line mutations of VHL and erythrocy-
tosis. CP was first described in the mid-1970s and is endemic in the
Polycythemia is also associated with Cushing syndrome, acromegaly, Chuvash population of the Russian republic. The serum EPO con-
and primary aldosteronism. Secondary polycythemia can also be seen centration in affected individuals is elevated compared with healthy
in 24% of older hypogonadal men receiving long-term androgen- first-degree family members, although some patients may have
replacement therapy and a significant number of competitive athletes normal serum EPO levels. They also have elevated levels of VEGF
taking anabolic steroids. For instance, in a small study of professional and plasminogen activator inhibitor-1. The erythroid progenitors of
bodybuilders, 67% of those examined had hematocrit levels above patients with CP are also hypersensitive to EPO; thus, CP has
50%. The effectiveness of drug screening in athletic competitions is characteristics of both primary and secondary polycythemias. A
demonstrated by the very low rate of positive test results for androgens homozygous missense mutation in the VHL gene, VHL598C→T
(<2% of 170,000 tests) on random testing at the Olympic Games mutation, has been identified in CP patients. The disorder is charac-
and other international events. Despite previous assertions regarding terized by high hemoglobin levels (usually >20 g/L), increased plasma
increased EPO excretion after androgen therapy, none of the athletes EPO levels, varicose veins, vertebral hemangiomas, low blood pres-
examined had elevated levels of EPO. Recombinant human EPO has sure, and an elevated concentration of VEGF. The defective VHL
also been abused by athletes competing in endurance sports and can gene product is not capable of promoting the ubiquitin-mediated
be detected by analyzing the individual’s hematocrit level, reticulocyte degradation of HIF-1α and HIF-2α, thereby leading to increased
count, percentage of macrocytic RBCs, serum EPO level, serum levels of both of these proteins and increased elaboration of EPO.
transferrin receptor level, and electrophoretic mobility of the EPO The CP-VHL mutants have been shown to affect EPO signaling in
molecule (recombinant EPO is less negatively charged than endog- erythroid progenitor cells of patients with CP. JAK2 phosphorylation
enous EPO). of STAT5 triggers not only erythroid progenitor development but
also a negative feedback mechanism by transactivating the expression
of SOCS family members, which bind and inhibit activated JAKs by
Congenital Secondary Polycythemias promoting their ubiquination and protosomal degradation. The CP
mutation causes conformational changes, leading to a tight CP–
High-Oxygen-Affinity Hemoglobins and VHL–SOCS-1 association, thereby slowing phosphorylated JAK2
Bisphosphoglycerate Deficiency degradation. These events lead to hyperactivation of the JAK2–STAT
More than 100 mutations of hemoglobin lead to increased oxygen pathway in erythroid progenitor cells, causing their hypersensitivity
affinity and thus decreased oxygen delivery and compensatory poly- to EPO, which likely contributes to the excessive erythrocytosis
cythemia (see Chapter 43). These mutations involve either the α- or characteristic of CP. Inheritance occurs as an autosomal recessive, and
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β-chain globin chains. Such polycythemias are usually well tolerated the frequency of the allele has been estimated to be at 0.057 in the
in young patients but may lead to thrombotic complications in older Chuvash population. Several other similar types of mutations in VHL
patients. High-oxygen–affinity hemoglobin variants are transmitted have been described that have been observed in a variety of other
as autosomal dominants. Phlebotomy therapy of such patients has ethnic groups. A number of heterozygotes with erythrocytosis have
been reported to not be of any beneficial value and has been shown been reported, which can likely be accounted for by an as yet undis-
to decrease exercise tolerance. The best test to detect high-oxygen– covered additional defect. CP is associated with a high mortality rate
affinity hemoglobin relies on the determination of hemoglobin dis- from thrombotic and hemorrhagic vascular complications. Most
sociation kinetics and P 50 (partial pressure of O 2 at which hemoglobin patients complain of chronic headache, fatigue, and/or lower extrem-
is 50% oxygenated). If cooximetry is not available, the P 50 can be ity pain, and are noted to have lower blood pressures. Cerebrovascular
mathematically estimated from a venous blood gas measurement by events are especially common causes of death. The median age of
using a computer algorithm, which is available online. death from cerebrovascular events is 42 years. Estimated survival to
Whereas a P 50 O 2 below 17 mmHg is indicative of a mutant age 65 years is 29% for individuals with CP and 64% for age-matched
hemoglobin with high oxygen affinity, a level above 35 mmHg is community members. There is a perfect genotype–phenotypic cor-
strongly suggestive of a mutant hemoglobin with a low oxygen affin- relation, with all patients with CP being homozygotes for the muta-
ity. Hemoglobin electrophoresis is not a reliable screen to rule out tion. Interestingly, heterozygous carriers do not develop erythrocytosis
such a hemoglobin mutation because only about half of these mutants but do have lower blood pressures and do not seem to be at increased
are electrophoretically distinguishable. Hemoglobin electrophoresis risk for tumors, which contrasts with patients with VHL syndrome.
will reveal the presence of an abnormal hemoglobin only if the Patients with CP also have larger livers, spleens, and kidneys than
mutation leads to a change in electrical charge. If such a charge dif- control patients, which has been attributed to enhanced cellular
ferential is not present, high-performance liquid chromatography or proliferation caused by HIF-2α suppression of p21Cip1.
mass spectrometry followed by polymerase chain reaction (PCR)- Germ-line mutations of VHL alleles have been reported in several
directed sequencing will be required to establish the diagnosis. patients with apparent congenital polycythemia that had no evidence
A rare cause of congenital polycythemia is 2,3-bisphosphoglycerate of developing a tumor; some of these subjects had germ-line muta-
(2,3-BPG; previously known as 2,3-DPG) deficiency (see Chapter tions of both VHL alleles. Other subjects with congenital poly-
44). 2,3-BPG is synthesized in RBCs and binds to hemoglobin, cythemia of various ethnicities, including Pakistanis, Punjabis,
thereby reducing its affinity for oxygen. An absence of 2,3-BPG African–Americans, and whites, harboring homozygosity for the CP