Evaluation of Erythrocytosis (Polycythemia)

When an elevated red cell count, hemoglobin concentration, or hematocrit occurs unexpectedly, it raises the question of polycythemia, a term used to denote an absolute increase in circulating red cell mass (some use the term erythrocytosis for all increases in red cell mass except those with an autonomous etiology). The upper limit of normal for a hematocrit is 52% for men and 47% for women. In the context of marked dehydration or severe chronic lung disease, the elevation may come as no surprise. In the absence of obvious concurrent disease, a search for an important underlying illness (e.g., polycythemia vera, occult malignancy, right-to-left shunt, hemoglobinopathy) is warranted. The finding may even be spurious because of volume contraction. In most instances, the primary physician should be able to distinguish among the variety of causes on clinical grounds, aided by a few simple laboratory studies.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12)

An absolute increase in red cell mass may represent abnormal stem cell proliferation (as in polycythemia vera), a response to chronic hypoxemia (as in chronic lung disease), or a manifestation of renal disease or extrarenal malignancy.

Polycythemia Vera

Pathophysiology and Genetics

Polycythemia vera is one of the chronic myeloproliferative disorders (the others being essential thrombocytosis and myelofibrosis with myeloid metaplasia—see Appendix 80-1-80-80). It affects all marrow elements as a consequence of clonal proliferation of a multipotent hematopoietic stem cell. Genetic mutations in chromosome 9p have been observed. The majority of patients exhibit the V617F somatic mutation in the Janus kinase 2 (JAK2) gene, producing a cytoplasmic kinase causing cytokine-independent proliferation of marrow cell lines. The affected stem cells can proliferate in the absence of erythropoietin, but they also demonstrate hypersensitivity to it and other growth factors. Not only is red cell mass increased, but so are leukocyte and platelet counts; however, thrombopoietin levels are normal or increased despite the increase in platelets, due to an error in the normal feedback mechanism. Besides increases in numbers of all three marrow elements, other hematologic manifestations include extramedullary hematopoiesis, splenomegaly, hyperuricemia, a hypercellular bone marrow, an increased risk of thrombosis, and progression to myelofibrosis with myeloid metaplasia.

The V617F mutation is also found in persons with other myeloproliferative disorders, including primary myelofibrosis and acute myeloid leukemia; however, the JAK2 mutation is not found in all cases. In upwards of 40%, a mutation has been found in the gene encoding calreticulin (CALR—see Appendix 80-1-80-80). Most homozygous patients exhibit polycythemia vera or myelofibrosis; those with essential thrombocythemia usually do not, but a subset with JAK 12 exon mutations may develop V617F-negative polycythemia.

Clinical Presentation and Course

Population-based studies found an incidence in the United States of 2.3 per 100,000. The prevalence is higher because survival is prolonged in the majority of patients. The peak age at onset is 50 to 60 years. Some patients have a relatively benign course, with red cell volume controlled by occasional phlebotomy, but others experience a much more malignant illness characterized by recurrent thrombosis and evolution toward myeloid metaplasia, myelofibrosis, and acute leukemia. Population-based study suggested that the risks of progression and hematologic complications are low. Prior exposure to myelosuppressive therapy (see later discussion) is a risk factor for malignant transformation.

It is not surprising that the presence of true polycythemia is often unsuspected because symptoms develop gradually and are frequently vague and rather nonspecific. In early stages, the patient may be entirely asymptomatic, with an elevated hematocrit as the only manifestation. As the disease progresses, the white blood cell (WBC) and platelet counts also increase, and symptoms and signs ensue as the red cell volume expands. Most symptoms are attributable to hyperviscosity, hypervolemia, and the resultant sluggish blood flow, which develop when the hematocrit increases to greater than 55%. Disturbed hemostasis ensues, exacerbated by defective platelet function.

Patients may present with either thrombosis (often in uncommon sites, such as hepatic, mesenteric, or retinal veins) or bleeding in the form of epistaxis, menorrhagia, easy bruisability, or oozing from the gums. The patient with advancing disease has a deep red appearance; peripheral cyanosis and ecchymoses may be noted. Blood pressure is usually normal, but neurologic symptoms are common (e.g., headache, dizziness, vertigo, tinnitus, “fullness” of the head, and blurred vision). Patients may complain of angina pectoris or claudication when coexisting atherosclerotic disease is present. Generalized weakness, fatigue, sweating, and lassitude are frequently reported. Gastrointestinal complaints may predominate (e.g., fullness, belching, epigastric or left upper quadrant discomfort); hepatomegaly is present in 40% of cases and splenomegaly in 70%. A classic symptom is pruritus after bathing, believed to be caused by abnormal histamine release. In addition, gouty joint symptoms occur in the context of marked secondary hyperuricemia caused by increased cell turnover.

Typically, the serum hemoglobin concentration is greater than 18.5g/dL in men and greater than 16.5g/dL in women, or an unexplained increase in hemoglobin concentration of 2g/dL is present. In about 60% to 70% of cases, the WBC count increases to greater than 12,000/mm³. More than half of patients experience an increased platelet count. The red cells appear normochromic and normocytic unless iron deficiency develops, in which case the red cells may appear microcytic and hypochromic. The erythrocyte sedimentation rate is frequently very low. Erythropoietin levels are never elevated (in contrast to erythropoietin levels in other forms of polycythemia) and are often low. Leukocyte alkaline phosphatase concentrations are increased in 80% of cases, as are vitamin B₁₂ levels, a consequence of an increase in vitamin B₁₂-binding proteins.

Reactive Erythrocytosis (Secondary Polycythemia)

Chronic hypoxemia triggers erythropoietin production, which in turn stimulates the marrow production of red cells. The increase is usually an appropriate physiologic response to tissue hypoxia and occurs when the arterial oxygen tension (PaO₂) continually decreases to less than 55 mm Hg or, more precisely, when the arterial oxygen saturation (SaO₂) decreases to less than
92%. Residence at a high altitude and severe pulmonary disease are common causes of chronic hypoxemia. Other etiologies include cyanotic heart disease with right-to-left shunt, heavy cigarette smoking (associated with excessive levels of carboxyhemoglobin), and a hemoglobin variant that poorly releases oxygen to tissues.

Pathologic Secondary Erythrocytosis

When erythropoietin production is increased in the absence of tissue hypoxemia, then pathologic secondary polycythemia may ensue. Renal disease and a host of extrarenal malignancies have been implicated. Such instances of inappropriate erythropoietin production are unusual, but their occurrence can be an early clue of underlying disease. In about 1% to 3% of renal cell carcinomas, erythrocytosis is a manifestation, occurring at a time when cure is possible. Focal glomerulonephritis, hydronephrosis, renal artery stenosis, and polycystic kidney diseases are occasionally associated with elevations in erythropoietin and erythrocytosis. The mechanism is believed to involve a reduction in blood flow to renal tissue involved in erythropoietin production. Huge uterine myomas, cerebellar hemangiomas, and hepatomas are also causes, although the mechanisms are unclear; up to 10% of patients with hepatoma in one series had erythrocytosis. In rare instances, an increase in circulating androgens is associated with polycythemia.

Relative (Spurious) Erythrocytosis

Relative spurious erythrocytosis is a term that denotes a heterogeneous set of conditions, characterized by an increase in hematocrit without an increase in red cell mass. The most common and usually self-evident cause is volume depletion. The situation is more controversial with regard to a group of patients who appear to have a normal to increased erythrocyte mass and a low to normal plasma volume (also referred to as Gaisböck syndrome or stress erythrocytosis). There is some debate on the actual existence of such a state, but it has been reported in obese, tobacco-smoking, middle-aged, hypertensive men. Such men manifest an increased risk for thromboembolization.

DIFFERENTIAL DIAGNOSIS (2,12)

Patients with erythrocytosis can be separated on the basis of their underlying pathophysiology into three diagnostic categories: (a) polycythemia vera, (b) secondary erythrocytosis, and (c) relative (spurious) erythrocytosis. Secondary erythrocytosis can be subdivided into physiologic and pathologic varieties (Table 80-1).

WORKUP (2,4,7,8,12, 13, 14 and 15)

The cause of erythrocytosis can usually be identified clinically with the aid of a few well-selected laboratory tests. The first task is to rule out decreased plasma volume and then to determine whether the true increase in hematocrit is a physiologic response or a pathologic process.

History

The history should first be checked for risk factors for volume depletion (e.g., diuretic use, vomiting, diarrhea) and for precipitants of chronic hypoxemia (e.g., residence at a high altitude, known cyanotic heart disease, smoking more than two packs per day, chronic lung disease). Inquiry into a familial occurrence of polycythemia helps to identify an abnormal hemoglobin, and a history of renal disease is also useful for the recognition of pathologic secondary erythrocytosis. Important clues for polycythemia vera are easy bruising, bleeding, and thrombosis, especially if the clotting involves an unusual site (e.g., retina, hepatic or portal vein, mesenteric vasculature). Symptoms of hyperviscosity should be reviewed, although most are nonspecific (e.g., lassitude, headache, sweating). It is common to ask about pruritus worsened by bathing, a classic symptom of polycythemia vera. Any report of abdominal discomfort should be noted because it might be a manifestation of the organomegaly associated with polycythemia vera.

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