What are the causes of elevated hemoglobin?

Causes of Elevated Hemoglobin

Elevated hemoglobin results from either true increases in red blood cell mass (absolute polycythemia) or plasma volume depletion (relative polycythemia), with causes ranging from primary bone marrow disorders to secondary physiologic responses and hemoconcentration. 1

Relative Polycythemia (Hemoconcentration)

Volume depletion from dehydration, diuretic use, or acute fluid losses concentrates red blood cells, producing a spurious rise in measured hemoglobin without a true increase in red cell mass. 1 Before pursuing an extensive work-up for true polycythemia, clinicians should first exclude hemoconcentration as a reversible cause of elevated hemoglobin. 1

• Dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) can cause relative polycythemia due to plasma volume depletion. 2

Primary Polycythemia

Polycythemia Vera

Polycythemia vera is a myeloproliferative neoplasm caused by JAK2 mutations (present in >95% of cases) that results in erythropoietin-independent red cell production. 2, 3 The diagnosis requires both major WHO criteria (elevated hemoglobin >18.5 g/dL in men or >16.5 g/dL in women AND presence of JAK2 mutation) plus at least one minor criterion, OR the first major criterion plus at least two minor criteria. 2

• Minor criteria include bone marrow hypercellularity with trilineage growth, subnormal serum erythropoietin level, and endogenous erythroid colony formation. 2
• JAK2 mutation testing (both exon 14 V617F and exon 12) should be performed as the cornerstone first-line test for distinguishing polycythemia vera from secondary erythrocytosis. 2
• A rare subset of patients may present with masked polycythemia vera, showing normal hemoglobin and hematocrit due to blood dilution or coincidental blood loss anemia, yet still harbor underlying disease. 4

Hereditary Erythrocytosis

Hereditary methemoglobinemia caused by NADH cytochrome b5 reductase deficiency (CYB5R3 gene mutations) often exhibits erythrocytosis, with patients showing MetHb levels above 25% and symptoms including cyanosis, headache, fatigue, and dyspnea. 5

• High-oxygen-affinity hemoglobin variants, erythropoietin receptor mutations, and Chuvash polycythemia (von Hippel-Lindau gene mutation) are rare genetic disorders causing elevated hemoglobin levels. 2, 6
• Primary familial and congenital polycythemia may result from truncated erythropoietin receptors lacking the cytoplasmic carboxy-terminal negative growth regulatory domain. 6

Secondary Polycythemia (Hypoxia-Driven)

Chronic Respiratory Disorders

Chronic obstructive pulmonary disease and other chronic respiratory disorders stimulate erythropoiesis through sustained hypoxemia, leading to modestly elevated hemoglobin levels. 1 Obstructive sleep apnea produces nocturnal hypoxemia that drives erythropoietin production. 2

• If initial workup suggests absolute erythrocytosis, consider sleep study if nocturnal hypoxemia is suspected and evaluate for potential secondary causes such as smoking or COPD. 2

Cardiac Conditions

Cardiac conditions that produce right-to-left shunting (e.g., certain congenital heart defects) reduce tissue oxygen delivery and trigger compensatory erythrocytosis. 1 Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport. 2

Smoking

Smoking leads to "smoker's polycythemia" due to chronic tissue hypoxia, with carbon monoxide exposure from smoking stimulating erythropoietin production. 2 This resolves with smoking cessation. 2

High Altitude

Altitude adaptation can cause normal increases in hemoglobin levels, with specific adjustments needed for altitude ranging from +0.2 g/dL at 1,000 meters to +4.5 g/dL at 4,500 meters. 2

Secondary Polycythemia (Hypoxia-Independent)

Testosterone Therapy

Testosterone replacement therapy raises hemoglobin by approximately 15–20% in treated individuals. 1 Intramuscular testosterone injections are associated with a markedly higher incidence of erythrocytosis (≈44%) compared with transdermal preparations (≈15%). 1

• Hematocrit values exceeding 52% occur more frequently with injectable testosterone and represent a significant clinical concern, especially in older adults with underlying vascular disease. 1
• Supraphysiologic testosterone dosing (e.g., >300 mg weekly) substantially amplifies the risk of erythrocytosis beyond that seen with physiologic replacement regimens. 1

Erythropoietin-Stimulating Therapy

In patients with chronic kidney disease, epoetin therapy raises hemoglobin toward target levels typically set between 10–12 g/dL. 1 Monitoring is essential because hemoglobin values that exceed the target range may increase cardiovascular risk. 1

Malignancies

Certain malignancies, such as renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma, can produce erythropoietin independently, causing elevated hemoglobin levels. 2

Physiological Variations

Males typically have higher hemoglobin levels than females, with normal hemoglobin levels varying by sex. 2 Adult males/post-menopausal females typically have a hemoglobin level of 15.5 ± 2.0 g/dL and a hematocrit of 47 ± 6%, while menstruating females have a hemoglobin level of 14.0 ± 2.0 g/dL and a hematocrit of 41 ± 5%. 2

• These gender differences in hemoglobin and hematocrit levels emerge at puberty due to the effects of testosterone and estrogen. 2
• In women aged ≥70 years, the 95th percentile for hemoglobin is approximately 15.2–15.6 g/dL. 2

Common Pitfalls

A hematocrit threshold of >52% should prompt therapeutic intervention (e.g., phlebotomy, adjustment of testosterone dose, or modification of erythropoietin therapy), particularly in patients receiving testosterone or erythropoiesis-stimulating agents. 1 However, therapeutic phlebotomy is indicated only when hemoglobin is greater than 20 g/dL and hematocrit is greater than 65%, with associated symptoms of hyperviscosity in the absence of dehydration. 2

• Repeated routine phlebotomies should be avoided due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke. 1
• Iron deficiency can coexist with erythrocytosis, particularly in cyanotic heart disease or polycythemia vera, causing microcytic polycythemia with elevated RBC count but reduced hemoglobin. 2