Polycythemia

Polycythemia is defined as an elevation in hemoglobin levels (>16.0 g/dL in women or >16.5 g/dL in men) or hematocrit (>48% in women or >49% in men). Polycythemia can be relative secondary to plasma volume depletion or absolute due to an increase in red blood cell mass. Measurement of serum erythropoietin (EPO) can differentiate between primary (EPO-independent) polycythemia, which has a low EPO level, and secondary (EPO-dependent) polycythemia, which has a high EPO. The reference range for serum erythropoietin is 3-18 IU/L. 

The workup of polycythemia begins with ruling out polycythemia vera (PV), which is a chronic myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells leading to increased red cell mass. Erythrocytosis occurs autonomously, resulting in down regulation of EPO production and low or normal serum EPO levels. In contrast, secondary erythrocytosis is associated with increased EPO levels. 

A suppressed serum EPO level of <3.3 IU/L has a sensitivity of 89% for distinguishing PV from other causes of polycythemia. Conversely, an EPO level >3.3 IU/L has a sensitivity of 97% for detecting secondary polycythemia. An EPO level <1.4 IU/L is 100% specific for a diagnosis of PV, while an EPO level of >13.7 IU/L is 100% specific for the diagnosis of secondary polycythemia. 

More than 95% of patients with PV have a mutation in exon 14 of the Janus kinase 2 (JAK2) gene. Patients should be tested for this variant to distinguish PV from secondary polycythemia. The presence of a JAK2 V617F mutation has a sensitivity of 97% and specificity of 100% for distinguishing polycythemia vera from other causes of polycythemia. 

If V617F is not detected, patients with polycythemia and suppressed EPO levels should be tested for less common mutations in exon 12 of the JAK2 gene. Approximately 3% of patients with PV have a mutation in JAK2 exon 12. PV can be confirmed with a bone marrow biopsy. 

PV is ruled out if a JAK2 mutation is not detected and serum EPO level is not suppressed. These patients should be evaluated for congenital mutations that lead to hypersensitivity in EPO signaling such as the EPO receptor, hypoxia inducible factor 2a, and proline hydroxylase domain-2. 

If all testing results for primary causes are negative, then the patient should be evaluated for secondary causes of polycythemia. Secondary erythrocytosis is EPO-driven and characterized by elevated serum EPO levels. The workup of secondary polycythemia should proceed according to the prevalence of known causes. Hypoxia is the major stimulus for EPO production. Cigarette smoking should be ruled out because it is the most common cause of secondary polycythemia. Carbon monoxide and high altitude exposure are other causes of hypoxia. A decrease in arterial oxygen saturation is diagnostic of hypoxic polycythemia. A partial arterial oxygen pressure of >67 mm Hg or an oxygen saturation of >95% on arterial blood gas results rules out hypoxia as a cause of polycythemia. If these etiologies are ruled out, patients should be worked up for underlying cardiopulmonary diseases, including obstructive sleep apnea. Approximately 5 to 10% of patients with obstructive sleep apnea have polycythemia. 

Less common causes of secondary polycythemia include exogenous administration of recombinant EPO for blood doping, exogenous androgen administration and anabolic steroid use. If the cause of polycythemia still remains elusive, abdominal imaging may be done to evaluate for EPO-producing tumors such as uterine leiomyomata, renal cell carcinoma, hepatocellular carcinoma, and hemangioblastoma. 

High oxygen affinity hemoglobinopathy can be detected by hemoglobin electrophoresis and a P50 hemoglobin-oxygen dissociation curve. If the P50 value is decreased, the diagnosis may be high oxygen affinity hemoglobin. A family history of polycythemia should prompt screening for hereditary polycythemia, most notably von Hippel Lindau gene mutations that predispose to Chuvash polycythemia. 

References

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MossuzP,GirodonF,DonnardM,etal. Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis. Haematologica. 2004;89(10):1194-1198.  

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