Clinical Information

Erythrocytosis (ie, increased RBC mass, elevated RBC count, and elevated hemoglobin and hematocrit) may be primary, due to an intrinsic defect of bone marrow stem cells, as in polycythemia vera (PV); or secondary, in response to increased serum 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 these common causes of secondary erythrocytosis are excluded, a heritable cause involving hemoglobin or erythrocyte regulatory mechanism may be suspected.

Unlike PV, hereditary erythrocytosis is not associated with the risk of clonal evolution and should present with isolated erythrocytosis that has been present since birth. A rare subset of cases is associated with pheochromocytoma and paraganglioma formation later in life. Hereditary erythrocytosis may be caused by mutations in one of several genes and inherited in either an autosomal dominant or autosomal recessive manner. A family history of erythrocytosis would be expected in these cases, although de novo mutations have also been reported.

Genetic mutations causing hereditary erythrocytosis have been found in genes coding for alpha and beta hemoglobins, hemoglobin stabilization proteins (eg, 2,3-bisphosphoglycerate mutase: BPGM), the erythropoietin receptor (EPOR), and oxygen-sensing pathway enzymes (hypoxia-inducible factor: HIF, prolyl hydroxylase domain: PHD, and von Hippel Lindau: VHL), see table. High-oxygen-affinity hemoglobin variants and BPGM abnormalities result in a decreased p50 result, whereas those affecting EPOR, HIF, PHD, and VHL have normal p50 results. The true prevalence of mutations causing hereditary erythrocytosis is unknown.

Table. Erythrocytosis Testing