Advertisement

A Common, Under-recognized Cause of Elevated Serum Erythropoietin

      To the Editor:
      When evaluating etiologies of erythrocytosis, serum erythropoietin is used to distinguish polycythemia vera from secondary causes. Paraneoplastic polycythemia is a rare cause of secondary polycythemia, most frequently associated with renal cell or hepatocellular carcinomas. This diagnosis should be considered in patients with erythrocytosis and an inappropriately normal or high erythropoietin, in the absence of physiologic stimuli for erythropoietin overproduction.

      Case Report

      A 49-year-old man was incidentally found to have an elevated hemoglobin level of 17.1 g/dL (reference 12.5-17.0 g/dL) and hematocrit of 51.5% (reference 36%-50%). Erythropoietin level was markedly elevated at 171 mIU/mL (reference 4.2-27.8 mIU/mL). The patient had no history of hypoxia, tobacco use, and no family history of cancer, hemoglobinopathies, or genetic disorders. He was taking no medications. On physical examination, he was normotensive, with normal oxygen saturation, and no abnormal physical findings. Although subsequent studies showed hemoglobin in the high-normal range, erythropoietin remained markedly elevated (92.5-189 mIU/mL). To evaluate for an occult renal or renovascular source, renal venous sampling was performed, with similarly elevated erythropoietin levels bilaterally. Magnetic resonance imaging of the abdomen showed no renal, adrenal, or liver masses; positron emission tomography–computed tomography was similarly unrevealing. Brain magnetic resonance imaging showed no evidence of cerebellar hemangioblastoma. No erythropoietin receptor or Von Hippel-Lindau gene mutations were found.
      Serendipitously, our institution's laboratory was transitioning between 2 commercial erythropoietin assays widely used in the US, both of which employ antibody-based capture to measure erythropoietin.
      • Owen W.E.
      • Roberts W.L.
      Performance characteristics of the IMMUNLITE 2000 erythropoietin assay.
      To ensure assay reproducibility, the laboratory tested samples from 126 patients with both assays, and 2 patients, including ours, showed widely discrepant results. While the patient's erythropoietin was abnormally high with one immunoassay,
      • Owen W.E.
      • Roberts W.L.
      Performance characteristics of the IMMUNLITE 2000 erythropoietin assay.
      it was normal with the other assay. Maneuvers to assess for heterophile and human anti-animal antibody interference with linear dilutions and blocking agents failed to resolve the discrepancy. There was no interfering serum paraprotein. To measure erythropoietin using another technology, the sample was sent for protein electrophoresis to an independent laboratory specializing in “blood doping”; active erythropoietin species were confirmed to be normal, affirming that the high measurements were spurious. A review of the patient's 4-year-long evaluation confirmed that all prior erythropoietin levels measured by 2 independent, major commercial laboratories, as well as our own, were performed using the same clinical immunoassay, consistently producing falsely elevated results.

      Discussion

      Although heterophile antibody and other nonspecific interference are a widely acknowledged limitation of immunoassays in the laboratory medicine community,
      • Marks V.
      False-positive immunoassay results: a multicenter survey of erroneous immunoassay results from assays of 74 analytes in 10 donors from 66 laboratories in seven countries.
      it is under-recognized by internists. Many routine clinical screening tests, such as hormone levels, viral serologies, tumor markers, and biomarkers of cardiac injury may be affected by assay interference, potentially leading to unnecessary procedures, anxiety, expense, and patient harm
      • Cole L.A.
      • Rinne K.M.
      • Shahabi S.
      • Omrani A.
      False-positive hCG assay results leading to unnecessary surgery and chemotherapy and needless occurrences of diabetes and coma.
      (Table). A physician should suspect an erroneous result if it contradicts the clinical presentation; however, a false result of an appropriately ordered test may well be compatible with the clinical history, and may be less likely to engender skepticism. Confirmation with alternative technologies should be sought, recognizing that it may not be possible or practical in all cases. Our laboratory found discrepant erythropoietin results in 2 of 126 samples, consistent with the one per 98 samples heterophile interference rate in the study that established this assay as suitable for routine clinical use.
      • Owen W.E.
      • Roberts W.L.
      Performance characteristics of the IMMUNLITE 2000 erythropoietin assay.
      The 1% assay interference rate makes false-positive results a far more common cause of elevated erythropoietin than an occult erythropoietin-producing tumor. Our case highlights the need for greater safeguards for tests employed in routine clinical practice, and calls for improved result reporting to increase the awareness of assay limitations among clinicians.
      TableCommon Clinical Immunoassays Known to be Affected by Heterophile Antibody Interference
      HormonesTumor Markers
       Adrenocorticotropin hormone (ACTH) Alpha fetoprotein (AFP)
       Calcitonin Cancer antigen 125 (CA 125)
       Cortisol Cancer antigen 19-9 (CA 19-9)
       Erythropoietin Carcinoembryonic antigen (CEA)
       Follicular-stimulating hormone (FSH) Chromogranin A
       Growth hormone (GH) Human chorionic gonadotropin (HCG)
       Human chorionic gonadotropin (HCG) Prostate-specific antigen (PSA)
       Inhibin A
       Luteinizing hormone (LH)Drug Levels
       Parathyroid hormone (PTH) Digoxin
       Prolactin Tacrolimus
       Serum antimüllerian hormone (AMH)
       TestosteroneAutoimmune Serologies
       Thyroglobulin Anti-dsDNA antibodies
       Thyroid-stimulating hormone (TSH)
       ThyroxineViral Serologies
       Hepatitis B antigen
      Other Tests Human immunodeficiency virus (HIV) serologies
       Ferritin
       MyoglobinMarkers of Myocardial Injury
       Tryptase Creatine kinase-MB (CK-MB)
       Troponin-I

      References

        • Owen W.E.
        • Roberts W.L.
        Performance characteristics of the IMMUNLITE 2000 erythropoietin assay.
        Clin Chim Acta. 2004; 340: 213-217
        • Marks V.
        False-positive immunoassay results: a multicenter survey of erroneous immunoassay results from assays of 74 analytes in 10 donors from 66 laboratories in seven countries.
        Clin Chem. 2002; 48: 2008-2016
        • Cole L.A.
        • Rinne K.M.
        • Shahabi S.
        • Omrani A.
        False-positive hCG assay results leading to unnecessary surgery and chemotherapy and needless occurrences of diabetes and coma.
        Clin Chem. 1999; 45: 313-314