Idiopathic erythrocytosis: a disappearing entity

Abstract

Erythrocytosis results when there is an increased red cell mass and thus an increased hemoglobin. The causes can be divided into primary intrinsic defects of the erythroid progenitor cell and secondary defects, where factors external to the erythroid compartment are responsible. Both can then be further divided into congenital and acquired categories. Congenital causes include mutations of the erythropoietin receptor and defects of the oxygen-sensing pathway including VHL, PHD2 and HIF2A mutations. When fully investigated there remain a number of patients in whom no cause can be elucidated who are currently described as having idiopathic erythrocytosis. Investigation should start with a full history and examination. Having eliminated the common entity polycythemia vera, further direction for investigation is guided by the erythropoietin level. Clinical consequences of the various erythrocytoses are not clear, but in some groups thromboembolic events have been described in young patients. Evidence is lacking to define best management, but aspirin and venesection to a target hematocrit should be considered.T he average adult produces 2.3 × 10 6 red cells every second.1 These red cells contain hemoglobin (Hb), which is the means whereby oxygen is supplied to the tissues. There are precise homeostatic mechanisms to ensure sufficient, but not excess, red cell production. Any imbalance in the homeostatic mechanisms can lead to excess red cell production known as erythrocytosis.The exact extent of an erythrocytosis is ascertained by measuring the red cell mass. The red cell mass is defined as increased if it is greater than 125% above that expected for sex and body mass. 2 If this occurs, then the subject has an absolute erythrocytosis. The presence of an absolute erythrocytosis is reflected in the fact that the Hb and hematocrit (Hct) are also increased. The various parameters do not completely reflect each other as other factors may affect the measurements; however, an Hct of 0.60 or greater is always associated with an increased red cell mass. 3 An Hb above 18.5 g/dL in a male or 16.5 g/dL in a female or an Hct above 0.52 in a male or 0.48 in a female suggests that there is an erythrocytosis. It may be necessary to carry out a red cell mass to establish unequivocally that an absolute erythrocytosis is present. Classification of ErythrocytosesAn erythrocytosis can be classified depending on the identified cause. The main division is on the basis of primary causes, where an intrinsic defect in the erythroid progenitor cell is associated with an enhanced response to cytokines; or secondary, where the increased red cell production is driven by factors external to the erythroid compartment, such as increased erythropoietin (EPO) production for any reason. Primary and secondary causes can be classified further as either congenital or acquired ( Table 1). Primary Erythrocytosis Congenital Erythropoietin Receptor MutationsThe cytokine EPO binds to the EPO receptor on the surface of the erythroid cell. When this occurs a pho...

Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations

“…3,9 About two thirds of these patients have inappropriately normal or elevated erythropoietin levels suggesting a defect in oxygen-sensing or oxygen delivery pathways. Most patients have early-onset disease and/or often a family history, suggesting a high probability of genetic etiology.…”

“…8 Some patients, particularly those with polycythemia vera and some forms of genetic erythrocytosis, have increased incidences of both arterial and venous thromboembolic events. 9 Other congenital lesions include high oxygenaffinity hemoglobinopathies or 2,3-bisphosphoglycerate deficiency, [10][11][12] caused by mutations in globin genes (HBA1, HBA2, HBB) or the BPGM gene, respectively. These genes belong to key pathways involved in the pathogenesis of erythrocytosis e.g.…”

Isolated erythrocytosis: study of 67 patients and identification of three novel germ-line mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene

“…These patients typically present without splenomegaly and may show a wide range of serum erythropoietin (Epo) levels, reflecting the heterogeneous genetic origins of this disorder. [1][2][3] In the presence of JAK2 mutations, these patients are usually classified as polycythemia vera (PV) according to the WHO 2008 classification. 4 In IE without JAK2 mutations, the defect may be intrinsic to the erythroid progenitor cells.…”

A Japanese Family with Congenital Erythrocytosis Caused by Haemoglobin Bethesda

“…The presence of a high oxygen affinity Hb variant or 2,3-biphosphoglycerate mutase (BPGM) deficiency impairs oxygen release to the tissues. The oxygen dissociation curve (ODC) is shifted to the left and leads to inappropriately raised serum EPO levels with high Hb values (1)(2)(3)(4). In this report, we describe a Japanese family who carry the Hb Bethesda variant, a haemoglobinopathy with a high oxygen affinity, and demonstrate the importance of determining the P50 value in the ODC for an accurate diagnosis.…”

“…Acquired secondary erythrocytosis is the most common form and can be caused by a high-altitude habitat, heavy smoking, or various disorders (e.g., chronic obstructive pulmonary disease, congenital heart disease, and EPO-producing tumour) (1)(2)(3)(4). When these causes are excluded, a genetic cause involving haemoglobin (Hb) variants or the proteins of the oxygen-sensing pathway should be suspected, although these causes are rare (1)(2)(3)(4). The presence of a high oxygen affinity Hb variant or 2,3-biphosphoglycerate mutase (BPGM) deficiency impairs oxygen release to the tissues.…”