Erythropoietin Level

Erythropoietin is a glycoprotein hormone made mainly by peritubular interstitial cells of the renal cortex, with a smaller contribution from the liver. Falling tissue oxygen delivery raises its synthesis through stabilisation of hypoxia inducible factor 2, and it prevents apoptosis of erythroid progenitors. Serum concentration is measured by immunoassay. The test asks whether red cell mass is regulated appropriately.

In erythrocytosis, it shows whether the excess is autonomous (low level) or hormone driven (normal or raised). In anaemia, it shows whether the hormone response matches the degree of anaemia.

Most erythrocytosis in practice is secondary to smoking, sleep apnoea, lung disease, testosterone use or obesity, and erythropoietin helps find the minority with a clonal or genetic cause. It is not needed to diagnose anaemia of chronic kidney disease, which is diagnosed by exclusion.

Indications. Persistent erythrocytosis (haemoglobin over 165 g/L or haematocrit over 0.49 in men, haemoglobin over 160 g/L or haematocrit over 0.48 in women), suspected polycythaemia vera, suspected erythropoietin secreting tumour, suspected congenital erythrocytosis, and low risk myelodysplasia before erythropoiesis stimulating therapy.

Specimen. Serum or heparin plasma, separated promptly and frozen if testing is delayed. Collect before any transfusion or erythropoiesis stimulating agent, since the assay also measures recombinant hormone. Biotin supplements should be stopped for 24 hours for biotin based assays.

Reference range. About 4 to 25 mU/mL (equal to U/L) in healthy adults, assay specific. Secretion is pulsatile with a small diurnal variation.

Low (under the lower reference limit). Strongly supports polycythaemia vera when erythrocytosis is persistent, and a subnormal level is a minor diagnostic criterion. It also occurs in primary familial and congenital polycythaemia from EPOR gain-of-function variants.

Normal. Does not exclude polycythaemia vera, since a minority of patients have levels in the reference range. A JAK2 V617F or exon 12 mutation with a normal erythropoietin level still supports polycythaemia vera. Levels are also normal in relative erythrocytosis from plasma volume loss.

Raised or inappropriately normal (secondary or congenital).

• Hypoxic: chronic lung disease, sleep apnoea, obesity hypoventilation, high altitude, right-to-left cardiac shunt, smoking (carboxyhaemoglobin), high-oxygen-affinity haemoglobin variants.
• Renal: cysts, hydronephrosis, renal artery stenosis, renal cell carcinoma, post-transplant erythrocytosis.
• Tumours: hepatocellular carcinoma, cerebellar haemangioblastoma, uterine fibroma, phaeochromocytoma, parathyroid adenoma.
• Drugs: testosterone, anabolic steroids, erythropoiesis stimulating agents.
• Congenital oxygen sensing defects: VHL (Chuvash), EGLN1 and EPAS1 variants.

Combined approach.

• JAK2 mutation with a low level supports polycythaemia vera.
• No JAK2 mutation with a raised level needs a search for a secondary cause: oxygen saturation, carboxyhaemoglobin, sleep study, renal and hepatic imaging, haemoglobin oxygen affinity.
• No JAK2 mutation with a low or normal level and no cause needs JAK2 exon 12 testing, marrow examination and congenital erythrocytosis genes.

Critical findings needing immediate action. A raised level with erythrocytosis plus severe hypertension, flank pain or mass, a hepatic mass, or cerebellar symptoms needs prompt imaging and specialist assessment.

Erythropoietin rises exponentially as haemoglobin falls, so the level is read against the haemoglobin and not against the healthy range alone.

Appropriately raised. Iron deficiency (often several hundred mU/mL when haemoglobin is under 80 g/L), aplastic anaemia (often over 1000 mU/mL), haemolysis, megaloblastic anaemia, thalassaemia major, and pure red cell aplasia (very high).

Inappropriately low or normal. Chronic kidney disease (anaemia typically becomes significant when eGFR is under about 30 to 45 mL/min/1.73 m²), anaemia of chronic disease and inflammation, chemotherapy, myeloma, HIV, hypothyroidism, hypopituitarism, ACE inhibitor use, and low risk myelodysplasia.

Myelodysplasia. A level under 500 U/L with a low transfusion requirement predicts response to erythropoiesis stimulating therapy, and a level under 100 U/L predicts the best response. A level over 500 U/L predicts poor response.

Pitfalls.

• Recent erythropoiesis stimulating therapy raises the result, and recent transfusion suppresses it.
• Healthy reference ranges do not apply in anaemia.
• Assay differences limit comparison between laboratories.
• Biotin interference, haemolysed samples and prolonged storage at room temperature distort results.
• A level in the reference range does not exclude polycythaemia vera, and a low level does not prove it.

Special groups. Levels rise modestly in pregnancy and are higher in neonates. Older adults show a mild rise with age. In chronic kidney disease, measurement does not change management.

Follow up tests. JAK2 V617F and exon 12 mutation analysis, bone marrow aspirate and trephine biopsy, oxygen saturation, carboxyhaemoglobin, sleep study, haemoglobin oxygen affinity (P50), haemoglobin electrophoresis, renal and abdominal imaging, EPOR, VHL, EGLN1 and EPAS1 sequencing, iron studies, creatinine and eGFR, thyroid function tests, testosterone, urinary metanephrines when phaeochromocytoma is suspected.