Interpretive Handbook

Erythrocytosis (increased RBC mass or polycythemia) may be primary, due to an intrinsic defect of bone marrow stem cells (polycythemia vera: PV), or secondary, in response to increased erythropoietin (EPO) levels. Secondary erythrocytosis is associated with a number of disorders including chronic lung disease, chronic increase in carbon monoxide (due to smoking), cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other EPO-secreting tumors. When extrinsic causes of erythrocytosis are excluded, a heritable cause intrinsic to the RBC or erythrocyte regulatory mechanisms may be suspected.

Mutations in genes coding for hemoglobin (high-oxygen-affinity hemoglobin variants), hemoglobin-stabilization proteins (2,3 bisphosphoglycerate deficiency), the erythropoietin receptor and oxygen-sensing pathway enzymes (hypoxia-inducible factor, prolyl hydroxylase domain, and von Hippel Lindau) can result in erythrocytosis (see Table). 

The oxygen sensing pathway functions through an enzyme, hypoxia-inducible factor (HIF) that regulates RBC mass. A heterodimer protein comprised of alpha and beta subunits, HIF functions as a marker of depleted oxygen concentration. When present, oxygen becomes a substrate mediating HIF-alpha subunit degradation. In the absence of oxygen, degradation does not take place and the alpha protein component is available to dimerize with a HIF-beta subunit. The heterodimer then induces transcription of many hypoxia response genes including EPO. HIF-alpha is regulated by von Hippel-Lindau (vHL) protein-mediated ubiquitination and proteosomal degradation, which requires prolyl hydroxylation of the serine and histidine residues. Enzymes important in the hydroxylation of HIF are the prolyl hydroxylase domain proteins, which have 3 isoforms-PHD1, PHD2, and PHD3. The most significant isoform associated with erythrocytosis is PHD2. PHD enzymes are oxygen dependent and have an iron-containing active site. Ascorbic acid enhances, but is not essential for, the activity of PHD. Therefore, activity can be modulated by low iron and ascorbic acid levels as well as by low oxygen. Clinically significant PHD2 (official designation EGLN1 [egl nine homolog 1]) mutations are heterozygous and have been found in exons 1 through 4. These mutations result in amino acid substitutions and are associated with inappropriately normal EPO levels.

Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.

Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.

Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.

Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.