Diagnostic Considerations
Polycythemia vera (PV) must be differentiated from other causes of polycythemia. The polycythemias can be subdivided by etiology into 3 groups: apparent or relative polycythemia, primary polycythemia, and secondary polycythemia.
A quick way to screen for polycythemia vera without excessive diagnostic testing is to determine if a hereditary pattern to the erythrocytosis is present. Because polycythemia vera is an acquired disorder, a familial pattern weighs against such a diagnosis; familial polycythemia vera has been reported, but in contrast with other familial polycythemias, the family clustering of polycythemia vera is associated with absence of phenotype at birth and an acquired polycythemic phenotype later in life. Rather, the phenotype at birth suggests the diagnoses such as high-affinity hemoglobin mutations, low 2,3 bisphosphoglycerate levels (BPG), primary familial and congenital polycythemia (PFCP), Chuvash polycythemia or rare mutations of HIF2a, or proline dehydrogenase type 2 genes. These disorders should be referred to a hematologist who is an expert in this area for specialized diagnostic testing and management.
Apparent or relative polycythemia is due to a decrease in plasma volume with a normal red cell mass. It is associated with hypertension, obesity, dehydration and stress, among other causes. [17]
Primary polycythemia is caused by intrinsic hyperproliferation of the hematopoietic stem cell independent of erythropoietin (Epo) stimulation or with exaggerated response to a low Epo level. Polycythemia vera, in which the hematopoietic stem cell proliferates independently of erythropoietin, is the most common primary polycythemia. The defining features of polycythemia vera are described in the Introduction. Another primary polycythemia is PFCP. The defect in PFCP is hyper-responsiveness to erythropoietin. One of its genetic causes has been defined: a hyperfunctional Epo receptor (a gain-of-function mutation) involving deletion of the negative regulatory subunit of the erythropoietin receptor (EpoR). Other mutations independent of the EpoR mutation are present but are as yet undefined.
Unlike polycythemia vera, which is a clonal acquired genetic mutation that can progress to leukemia, PFCP is a nonclonal germ line mutation that does not progress to acute leukemia. PFCP also differs from polycythemia vera in that only the erythroid lineage is affected.
Secondary polycythemia is due to elevated levels of Epo that induce erythrocyte proliferation; however, at the time of presentation, the increased RBC mass might have reached an equilibrium, and the Epo level is often within normal limits. The normal Epo level, however, would be inappropriately high for the elevated hematocrit. High Epo results from physiologically appropriate or inappropriate causes.
Physiologically appropriate secondary polycythemias result from hypoxia. Hypoxia is the common endpoint of the various causes of physiologically appropriate secondary polycythemias.
High-altitude polycythemia occurs because of lower ambient pO2 resulting in tissue hypoxia. Acute compensation occurs through hyperventilation, but chronic compensation involves elevation of hematocrit (although the degree of response varies between individuals). Not all populations accommodate to high altitude by polycythemia. The Tibetans have a lower hemoglobin level than expected but have high levels of exhaled nitric oxide, which may be the end product of a process improving oxygen delivery by inducing vasodilation and increasing blood flow to the tissues.
In cardiopulmonary disease, impaired respiration and circulation result in tissue hypoxia and subsequently increased erythropoietin.
Smoking results in the formation of carboxyhemoglobin that does not carry oxygen and results in higher oxygen affinity in other hemoglobin molecules. This results in tissue hypoxia, which induces Epo production. The rise in hematocrit is compounded by the reduction in plasma volume due to smoking.
Defects in bisphosphoglycerate mutase and phosphofructokinase result in decreased 2,3 BPG. BPG is necessary for hemoglobin to transition from a high oxygen affinity state to a low oxygen affinity state. Thus a decreased BPG level results in tissue hypoxia in erythrocyte enzyme defect polycythemia
Individuals with hemoglobinopathy with high affinity mutations (autosomal dominant inheritance) are unable to transition from high oxygen affinity to low oxygen affinity states due to impaired intramolecular rotation or BPG binding. Deoxygenation is impaired in some cases.
Methemoglobinemia is usually due to a cytochrome b5 reductase (methemoglobin reductase) deficiency but can also be caused by various mutations of globin genes, such as Hemoglobin M.
Cobalt is believed to inhibit oxidative metabolism controlling Epo production. It is not effective treatment for anemia. Cobalt has been used as a foam stabilizer in beer and has been shown to cause an acquired polycythemia when unintentionally ingested in high amounts.
Physiologically inappropriate polycythemia is often due to exogenous sources of erythropoietin.
Several malignancies have been shown to produce erythropoietin. These include hepatoma, renal cell carcinoma and cerebellar hemangiomas. Uterine myomas have been reported to produce erythropoietin. However, another mechanism by which these often large bulky tumors produce erythrocytosis is mechanical interference with the blood supply to the kidneys resulting in false sensing of hypoxia and Epo production.
Endocrine disorders such as pheochromocytomas, aldosterone producing adenomas, Barter syndrome, and dermoid cysts of the ovary can result in inappropriate Epo through mechanical interference with renal blood supply or hypertensive damage to renal parenchyma resulting in false sensing of hypoxia by the kidneys and subsequent Epo production, functional interaction between aldosterone, renin and erythropoietin, and inappropriate Epo secretion by the tumor. Androgens increase hematocrit by 2 mechanisms: stimulation of Epo production and an independent hyperproliferative effect on erythrocyte precursors.
Chuvash polycythemia is an endemic polycythemia found on the west bank of the Volga River in the Chuvash Autonomous Republic in western Russia. It is an autosomal recessive disorder characterized by a mutation in the VHL gene that prevents ubiquitin degradation of hypoxia inducible factor (HIF)-1, resulting in upregulation of downstream target genes, including Epo production. As such, Chuvash polycythemia can be grouped with the secondary inappropriate polycythemias. But because of a second defect resulting in hyper-responsiveness to erythropoietin, not linked to the EpoR, it also has some features of primary polycythemia. Clinically, patients with Chuvash polycythemia have normal ABG, normal calculated p50 of hemoglobin, normal to increased Epo levels, and no abnormal hemoglobins.
Rare mutations of HIF2a or proline dehydrogenase type 2 genes are associated with secondary congenital polycythemia; because of their rarity, the phenotype is not fully elucidated as yet.
Renal polycythemia is due to Epo produced by renal cysts, polycystic disease, or hydronephrosis.
Erythrocytosis can occur after renal transplant and is thought to be due to increased activity of the angiotensin II-angiotensin receptor 1 pathway. Angiotensin II may also modulate release of Epo and insulinlike growth factor (IGF)-1. Venous canalization studies have shown the source to be the "nonfunctional" native kidneys. Removal of the native kidneys can normalize the hematocrit; however ACE inhibitors can also control this typically transient erythrocytosis, thus avoiding surgery.
Neonatal polycythemia is an appropriate secondary polycythemia due to increased oxygen affinity of fetal hemoglobin and subsequent tissue hypoxia. This response can become excessive and inappropriate in the setting of maternal diabetes or placenta to child transfusion.
Differential Diagnoses
-
Bone marrow film at 400X magnification demonstrating dominance of erythropoiesis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
