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Secondary Polycythemia: Practice Essentials, Pathophysiology, Etiology
The word polycythemia indicates increased red blood cells, white blood cells, and platelets. Most of the time, it is used in place of erythrocythemia, or pure red blood cell increase, such as in secondary polycythemia.
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Practice Essentials
In secondary polycythemia, the number of red blood cells (RBCs) is increased as a result of an underlying condition. Secondary polycythemia would more accurately be called secondary erythrocytosis or erythrocythemia, as those terms specifically denote increased red blood cells. [1] The term polycythemia is used appropriately in the myeloproliferative disorder called polycythemia vera, in which there are elevated levels of all three peripheral blood cell lines: RBCs, white blood cells, and platelets.
Secondary polycythemia most often develops as a response to chronic hypoxemia, which triggers increased production of erythropoietin by the kidneys. Hypoxemia-related causes of secondary polycythemia include obstructive sleep apnea, obesity hypoventilation syndrome, chronic obstructive pulmonary disease (COPD), and heavy tobacco smoking. Other causes include testosterone replacement therapy and anabolic steroid use. Patients who have arteriovenous or intracardiac shunting can present with polycythemia without hypoxemia. Erythropoietin-secreting tumors (eg, hepatocellular carcinoma, renal cell carcinoma, adrenal adenoma) cause some cases. [3, 4, 5, 6]
Secondary polycythemia must be differentiated from primary polycythemia and from relative polycythemia (in which RBC numbers are normal but plasma volume is contracted. In relative polycythemia, the reduction in plasma volume may be due to dehydration or to reduced venous compliance; the latter is also termed stress polycythemia or Gaisböck syndrome, and is typically seen in obese middle-aged men who are receiving a diuretic for treatment of hypertension. See Presentation and Workup.
To the extent that the increased RBCs alleviate tissue hypoxia, secondary polycythemia may in fact be beneficial. However, treatment with phlebotomy is indicated for patients with hematocrits higher than 60%-65%, who may experience symptoms such as impaired alertness, dizziness, headaches, and compromised exercise tolerance, and who may face increased risk for thrombosis, strokes, myocardial infarction, and deep venous thrombosis. Otherwise, secondary polycythemia is addressed by treating the underlying condition. See Treatment.
Pathophysiology
Increased hemoglobin and hematocrit values reflect an increase in the ratio of red blood cell mass to plasma volume. Any change in either the hemoglobin or the hematocrit can alter test results.
Relative polycythemia, or erythrocythemia, results from decreased plasma volume. A true polycythemia or erythrocythemia results from increased red blood cell mass. Therefore, hemoglobin and hematocrit levels alone cannot accurately help make this distinction. Direct measurement of red blood cell mass is necessary to differentiate these conditions.
In primary polycythemia, the disorder results from a mutation expressed within the hematopoietic stem cell or progenitor cells, which drives the overproduction and accumulation of red blood cells. The secondary polycythemic disorders may be acquired or congenital; however, they are driven by factors that are independent of the function of hematopoietic stem cells. Elevated hemoglobin levels due to chronic hypoxia in patients with chronic lung disorders such as COPD or sleep apnea are the result of an increased production of erythropoietin, which in turn causes increased production of red blood cells.
Etiology
Secondary polycythemia is defined as an absolute increase in red blood cell mass that is caused by enhanced stimulation of red blood cell production. [4] In contrast, polycythemia vera is characterized by bone marrow with an inherent increased proliferative activity. [2, 7, 8] Approximately two thirds of patients with polycythemia vera have elevated white blood cell (granulocyte, not lymphocyte) counts and platelet counts. [9] No other causes of polycythemia/erythrocytosis are associated with elevated granulocyte or platelet counts.
Enhanced erythroid stimulation can be a physiologic response to generalized or localized tissue hypoxia, [10] as in the following settings:
- Because of the decreased ambient oxygen concentration at high altitudes, people living in those locales can develop compensatory erythrocytosis as a physiologic response to tissue hypoxia. [11]
- Chronic obstructive pulmonary disease is commonly due to a large amount of ventilation in poor gas exchange units (high ventilation-to-perfusion ratios). [12]
- Alveolar hypoventilation can result from periodic breathing and oxygen desaturation (sleep apnea) or morbid obesity (Pickwickian syndrome).
- Cardiovascular diseases associated with a right-to-left shunt (arteriovenous malformations) can result in venous blood mixing in the arterial system and delivering low oxygen levels to tissues.
- Hemoglobin abnormalities associated with high oxygen affinity and congenital defects can lead to oxidized hemoglobin or methemoglobin. These conditions are usually familial.
- Exposure to carbon monoxide, such as by smoking or working in automobile tunnels, results in an acquired condition. [13, 14] Carboxyhemoglobin reduces the oxygen transport capacity of RBCs and reduces oxygen release into tissues.
Impaired perfusion of the kidneys, which may lead to stimulation of erythropoietin [EPO] production, is usually due to local renal hypoxia in the absence of systemic hypoxia. Conditions include the following:
- Arteriosclerotic narrowing of the renal arteries or graft rejection of a transplanted kidney can lead to impaired kidney perfusion.
- Aneurysms affecting the aorta and renal vessels can lead to kidney infarction and hypoxia.
- Focal glomerulonephritis has been associated with secondary polycythemia, although the mechanism for stimulation of EPO secretion in this condition remains unknown.
- Polycythemia occurring after kidney transplantation is not a rare event. The mechanisms involved have not been clearly demonstrated.
Inappropriate stimulation of EPO production
Inappropriate stimulation of EPO production may occur in the following settings:
- Benign renal lesions, such as hydronephrosis and cysts, can stimulate EPO production, possibly due to compromised renal blood flow by compressive or vasoconstrictive mechanisms.
- Malignant and benign tumors that secrete EPO have been observed in patients with renal carcinomas, cerebellar hemangioblastomas, adrenal carcinomas, adrenal adenomas, hepatomas, and uterine leiomyomas.
- Blood doping is an illegal practice. Competitive athletes have been known to attempt to maintain an advantage over their opponents by autologous blood transfusions or self-administration of recombinant EPO. Several deaths have been attributed to excessive blood doping.
- Illicit use of androgenic steroids to build muscles and strength can also increase red blood cell mass by stimulating endogenous serum EPO levels.
Congenital causes
Hemoglobin mutants associated with tight binding to oxygen and a failure to deliver oxygen in the venous blood can cause high EPO levels. The high level of EPO is compensatory to elevate hemoglobin levels to deliver an optimal amount of oxygen to the tissues. Hypoxia-inducible factor 1-alpha (HIF1-alpha) binds to the hypoxia-responsive element, which is downstream of the gene for EPO. The activity of HIF1-alpha is increased by a lowered oxygen tension.
A von Hippel-Lindau gene mutation results in polycythemia by altering the von Hippel-Lindau protein, which plays an important role in sensing hypoxia and binds to hydroxylated HIF1-alpha to serve as a recognition site of an E3-ubiquitin ligase complex. In this condition, and in hypoxia, the undegraded HIF1-alpha forms a heterodimer with HIF-beta and leads to increased transcriptions of the gene for EPO.
Chuvash polycythemia is caused by an autosomal recessive gene mutation on the von Hippel-Lindau gene, which results in the upregulation of the HIF1-alpha target gene and causes elevations in EPO levels. [15]
Low EPO-dependent polycythemias
These are called primary familial and congenital polycythemias. [16] The EPO receptor mutation results in a gain of function, and patients have normal-to-high hematocrit values and low EPO levels. [17] These conditions can be acquired from (1) insulin like growth factor-1 (IGF-1), a well-known stimulator of erythropoiesis, and (2) cobalt toxicity, which can induce erythropoiesis.
Testosterone-associated polycythemia
The administration of androgen esters to hypogonadal men can lead to polycythemia. However, the incidence of testosterone-associated polycythemia may be lower in men receiving pharmacokinetically steady-state delivery of testosterone formulations, as occurs following the subcutaneous implantation of testosterone pellets, than it is in men receiving intramuscular injections of shorter-acting androgen esters.
Ip and colleagues found that in men receiving long-acting depot testosterone treatment, the development of polycythemia (hematocrit > 50%) was predicted by higher trough serum testosterone concentrations but not by the duration of treatment. [18]
Ory et al reported that men who develop secondary polycythemia while on testosterone therapy are at increased risk of major adverse cardiovascular events and venous thromboembolic events during the first year of therapy. [19]
Other
Secondary polycythemia has been reported as a paraneoplastic phenomenon in patients with testicular cancer. The mechanism is not clear.
A case of pazopanib-related secondary polycythemia has been reported in a patient receiving treatment for myxofibrosarcoma. [20]
Epidemiology
The frequency of secondary polycythemia depends on the underlying disease. The mortality and morbidity of secondary polycythemia depend on the underlying condition.
Prognosis
The prognosis of patients with secondary polycythemia is driven by the underlying disorder. The polycythemia itself, when physiologic and not sufficiently extreme to cause significant hyperviscosity, generally has no effect on life span. However, patients with secondary polycythemia generally have a shorter survival following diagnosis than patients with polycythemia vera. This is believed to reflect the dire conditions that underlie many cases of secondary polycythemia.
At extreme levels of secondary polycythemia, patients can be at risk for thrombosis. Excessive polycythemia, usually defined as hematocrit levels higher than 65-70%, may result in increased whole blood viscosity. This, in turn, may lead to impaired blood flow locally, resulting in thrombosis. The risk is lower than with primary erythrocytosis but data are too sparse for accurate quantification.
Hyperviscosity may also lead to generalized sluggish blood flow, resulting in impaired tissue oxygenation in multiple organs, which may lead to decreased mentation, fatigue, generalized weakness, and poor exercise tolerance.
History
Patients with a high red blood cell mass usually have plethora or a ruddy complexion. However, if the polycythemia is secondary to hypoxia, as in venous-to-arterial shunts or compromised lung and oxygenation, patients can also appear cyanotic.
Increased red blood cell mass increases blood viscosity and decreases tissue perfusion. With impaired circulation to the central nervous system, patients may present with headaches, lethargy, and confusion or more serious presentations, such as stroke and obtundation. In addition, polycythemia potentially predisposes patients to thrombosis. [21]
Congenital heart diseases manifest at birth or in early childhood. In some cases, a family history of congenital heart disease may be present.
Patients with familial hemoglobinopathies that result in increased oxygen affinity usually have a family history of similar problems in several family members, although significant numbers of patients with congenital polycythemia have no family history of similar disorders. [22]
Chronic pruritus in the absence of a rash is more indicative of a primary myeloproliferative disorder than of secondary polycythemia.
Physical Examination
Plethora manifests as increased redness of the skin and mucosal membranes. This finding is easier to detect on the palms or soles, where the skin is light in dark-skinned individuals. Some patients may have acrocyanosis caused by sluggish blood flow through small blood vessels.
The presence of splenomegaly supports a diagnosis of polycythemia vera rather than secondary polycythemia. Cardiac murmurs and clubbing of the fingers may suggest a congenital heart disease.
Diagnostic Considerations
Secondary polycythemia is included as a key differential diagnosis in polycythemia vera clinical practice guidelines. [23]
An analysis of the cytokine production profiles of patients with secondary polycythemia found decreased plasma levels of interleukin-17A (IL-17A), interferon gamma (IFN-γ), IL-12p70, and tumor necrosis factor alpha (TNF-α) compared with polycythemia vera patients. These researchers suggested that the cytokine production profile may provide a potential diagnostic biomarker to distinguish secondary polycythemia from polycythemia vera. [24]
Differential Diagnoses
- Adrenal Carcinoma
- Adrenal Incidentaloma
- Assessment and Management of the Kidney Transplant Patient
- Atrial Septal Defect
- Chronic Obstructive Pulmonary Disease (COPD)
- Cor Pulmonale
- Dehydration
- Obstructive Sleep Apnea (OSA)
- Polycythemia Vera
- Pulmonary Arteriovenous Malformation (PAVM)
- Renal Arteriovenous Malformation
- Renal Artery Stenosis
- Renal Cell Carcinoma
- Surgery for Craniopharyngiomas
- Ventricular Septal Defect Surgery in the Pediatric Patient
Laboratory Studies
Testing for the JAK2 V617F mutation and an erythropoietin (EPO) level helps differentiate secondary polycythemia from polycythemia vera. [25, 26] Positive JAK2 V617F mutation status with a low EPO level confirms the diagnosis of polycythemia vera. If JAK2 V617F mutation testing is negative but the EPO level is low, then testing for other mutations in exon 12 and 13 of JAK2 helps identify a small minority of patients with polycythemia vera. JAK2 mutation testing also identifies the rare patients with polycythemia vera who have elevated EPO levels. [27] Patients with wild-type JAK2 and a normal or elevated EPO level have secondary polycythemia.
When repeated hematocrit levels exceed 52% in males and 47% in females, consideration should be given to measurement of red blood cell (RBC) mass and plasma volume. The RBC mass is increased if it exceeds 35 mg/kg in males and 31 mg/kg in females. However, data from the Polycythemia Vera Study Group showed that if the hematocrit value is 60% or higher, the RBC mass is always increased; formal RBC mass and plasma volume studies are unnecessary in those cases. [28]
As a practical note, most nuclear medicine departments perform RBC mass and plasma volume measurements very infrequently, which may raise questions about the reliability and validity of these studies. In addition, the studies involve radiolabeling of the patient's RBCs with chromium-51 (51Cr), and that radioisotope is not always available. [4] Plasma volume can be measured using albumin radiolabeled with iodine-131 (131I), similar to the process used with the RBC mass measurement. Plasma volume can also be calculated indirectly using total RBC mass and the hematocrit value.
Decreased plasma volume with a normal RBC mass indicates a relative polycythemia or erythrocytosis, similar to the increased hemoglobin and hematocrit levels associated with severe dehydration. Decreased plasma volume due to dehydration is the most common cause of elevated hemoglobin or hematocrit levels in the general population.
Measuring arterial oxygen saturation is important to exclude generalized hypoxemia as a cause of increased RBC mass. Further investigation may require performing the test while the patient is sleeping. Measured arterial oxygen saturations of less than 92% may be associated with the development of a secondary polycythemia.
Carboxyhemoglobin levels of greater than 8% in individuals who smoke or who may have occupational exposure to carbon monoxide may be associated with the development of polycythemia.
The hemoglobin-oxygen dissociation curve may be determined in patients with a lifelong history (particularly a familial history) of erythrocytosis with normal oxygen saturation and normal levels of 2,3-diphosphoglycerate.
Formulas are available in which the measured arterial and venous oxygen saturations can be used to calculate the partial pressure of oxygen (PaO2) at which hemoglobin is 50% saturated with oxygen. This partial pressure value is a good estimate of the entire oxygen dissociation curve, because the shape of the dissociation curve varies only minimally, even with very high and very low oxygen affinity hemoglobins.
Imaging Studies
An abdominal computed tomography (CT) scan or an intravenous pyelogram to investigate the kidneys and their function may be indicated in a minority of patients who may have a tumor or renal abnormalities that may be causing the polycythemia.
Medical Care
Correction of the underlying cause of secondary polycythemia is the most important element of management. This may include cessation of exogenous erythropoietin, repair of arteriovenous or intracardiac shunts, or removal of tumors that are secreting erythropoietin.
The development of secondary erythrocytosis in response to tissue hypoxia is physiologic and probably beneficial to many patients. The expanded red blood cell mass may partially or totally compensate for the lack of oxygen delivery and result in tissue oxygenation to its normal level.
At hematocrit levels higher than 60-65%, however, the compensatory increase in red blood cells reaches the limit of benefit and begins to compromise circulation because of hyperviscosity. The latter leads to greater tissue hypoxia and erythropoietin secretion, a continued increase in the number of red blood cells, and further impairment of circulation.
To restore viscosity and maintain circulation at its optimal level, phlebotomize or remove the offending red blood cells. Some patients with extreme secondary polycythemia have impaired alertness, dizziness, headaches, and compromised exercise tolerance. They may also be at increased risk for thrombosis, strokes, myocardial infarction, and deep venous thrombosis. These are the patients who require phlebotomy.
The optimal level of hematocrit is one that is as close as possible to normal without impairing the compensatory benefit of increased oxygen delivery. This may be determined individually by symptom relief or decompensation, depending on the viscosity level.
Repeated phlebotomies result in iron deficiency that can cause other symptoms. [29] This may limit or retard further erythropoiesis so that additional phlebotomies may not be necessary. Proper treatment of the underlying condition in polycythemia, when possible, is important, such as the following:
- Provide oxygen supplementation to patients with chronic obstructive pulmonary disease.
- Recommend weight loss in patients with obesity and hypoventilation.
- Recommend smoking cessation for patients with carboxyhemoglobin.
- Surgically correct arteriovenous shunts.
