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Pseudohypoglycemia

Robert A Gabbay, MD, PhD, Associate Professor of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Director, Penn State Diabetes Center, Hershey Medical Center, Pennsylvania State University College of Medicine
Irina Lendel, MD, Clinical Instructor in Endocrinology, Division of Endocrinology, Diabetes, and Metabolism, Milton S Hershey Medical Center; Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine; George T Griffing, MD, Professor of Medicine, Director of General Internal Medicine, St Louis University

Updated: Sep 21, 2007

Introduction

Background

In 1927, Falcon-Lesses reported the rapid disappearance of glucose in vitro in blood removed from patients with leukemic leucocytosis. Pseudohypoglycemia is not a clinical syndrome but rather a result of artifactually low glucose concentration due to glycolysis in vitro, mainly in the presence of leucocytosis, polycythemia, or both. It may occur when the separation of plasma from the formed elements of the blood is delayed.

Pathophysiology

Pseudohypoglycemia has been observed in patients with leukemias (eg, chronic lymphocytic leukemia) and leukemoid reaction (eg, eosinophilic leukemoid reaction due to an underlying poorly differentiated carcinoma). Low glucose concentration results from the metabolism of glucose in vitro by the large number of leucocytes present. In case reports, patients had a white blood cell count of 300,000/mm3 (99% lymphocytes) and above. A 90% lowering of glucose levels occurred when the blood was kept at room temperature for 2 hours. In a whole blood samples obtained from healthy persons and allowed to clot at room temperature, the serum glucose level in the specimens may decrease 7-20 mg/dL/h independent of initial glucose value. This can happen when blood samples contain high levels of other cell types as well (ie, reticulocytes, mature forms of red blood cells, parasites [trypanosomes]).

Pseudohypoglycemia has been observed in benign forms of leucocytosis (leukemoid reactions and hematopoietic cytokines—stimulated leukocytosis), regardless of the presence of symptoms. In such cases, glucose concentration is within reference ranges when plasma is promptly separated from the formed elements of blood.

Chronic hemolytic anemia in hemolytic crisis, accompanied by a high count of nucleated red blood cells, has been associated with pseudohypoglycemia. The abnormality was reversed with a decrease of nucleated red blood cell count to 3%.

In the setting of polycythemia vera, an 87% decrease in blood glucose levels over 4 hours in vitro was observed. Similar findings were reported in patients with secondary erythrocytosis.

Pseudohypoglycemia can occur in immunoglobulin M (IgM) macroglobulinemia (morbus Waldenström macroglobulinemia) when there is insufficient sampling of hyperviscous serum. In one case report, low glucose readings were no longer observed after plasmapheresis or appropriate dilution of the sample to a serum viscosity of 1.4-1.8 (as measured with a capillary Ostwald viscometer).

Pseudohypoglycemia in a setting of African trypanosomiasis is caused by in vitro utilization of glucose by the parasites.

The term clinical pseudohypoglycemia is used when patients with personality/psychological disorders report relief of symptoms (eg, mental dullness, disorientation, confusion, palpitations) after eating. Plasma glucose levels are within reference ranges in all such patients while they are symptomatic.

Pseudohypoglycemia on fingerstick glucose testing has been observed in settings of hypovolemic shock and Raynaud phenomenon. Venous glucose levels were normal in both settings.

Primary red cell disorders associated with decreased red blood cell survival and reticulocytosis may alter glycohemoglobin measurements making it appear low.

Clinical

Causes

Pseudohypoglycemia is caused by in vitro glycolysis in the presence of the following:

  • Leukocytosis
  • Polycythemia
  • Delay in the separation of plasma from formed blood elements
  • Chronic anemia in a hemolytic crisis
  • Trypanosomiasis

Differential Diagnoses

Hypoglycemia

Workup

Laboratory Studies

  • Venous plasma glucose concentration greater than 3.9 mmol/L (70 mg/dL) after an overnight fast are within reference ranges, those between 2.8 and 3.9 mmol/L (50-70 mg/dL) are suggestive of hypoglycemia (but can be normal, particularly in females), and those less than 2.8 mmol/L (50 mg/dL) indicate hypoglycemia if associated with symptoms.
  • The clinical diagnosis of hypoglycemia is established when symptoms are consistent with hypoglycemia, a low plasma glucose concentration is found, and symptoms subside in the presence of normal plasma glucose levels (Whipple triad).
  • Plasma insulin levels and levels of compensatory counterregulatory hormones, such as glucagon, cortisol, growth hormone, and catecholamines, are within reference ranges when pseudohypoglycemia is found.
  • The presence of severe leukocytosis or polycythemia in a complete blood count should raise the suspicion of pseudohypoglycemia.

Follow-up

Deterrence/Prevention

  • Refrigerate or add an antiglycolytic agent (sodium fluoride) to the samples.
  • Promptly separate plasma from the formed elements of the blood.

Miscellaneous

Special Concerns

Occasionally, neoplasms may cause episodes of true hypoglycemia by (1) releasing insulinlike compounds, as described for mesotheliomas of the retroperitoneal space, fibromas, and mesenchymal tumors; (2) rapid metabolism of glucose by large numbers of leukemic cells; (3) trapping of insulin by monoclonal IgG immunoglobulins in multiple myeloma; and (4) a deficiency in liver glucose-6-phosphatase or extensive liver involvement.

References

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  2. Astles JR, Petros WP, Peters WP, Sedor FA. Artifactual hypoglycemia associated with hematopoietic cytokines. Arch Pathol Lab Med. Aug 1995;119(8):713-6. [Medline].

  3. Canivet B, Elbaze P, Dujardin P. Pseudohypoglycemia in a patient with leukemia [letter]. Biomedicine. Dec 1981;35(7-8):203-4. [Medline].

  4. Elks ML. Pseudohypoglycemia in adult victims of adolescent incest. South Med J. Nov 1990;83(11):1338-40. [Medline].

  5. Farfel Z, Freimark D, Mayan H, Gafni J. Spurious hypoglycemia, hyperkalemia and hypoxemia in chronic hemolytic anemia. Isr J Med Sci. Nov 1990;26(11):606-10. [Medline].

  6. Glasheen JJ, Sorensen MD. Burkitt's lymphoma presenting with lactic acidosis and hypoglycemia - a case presentation. Leuk Lymphoma. Feb 2005;46(2):281-3. [Medline].

  7. Gregory JW, Aynsley-Green A. The definition of hypoglycaemia. Baillieres Clin Endocrinol Metab. Jul 1993;7(3):587-90. [Medline].

  8. Haibach H, Wright DL, Bailey LE. Pseudohypoglycemia in a patient with Waldenstrom's macroglobulinemia, an artifact of hyperviscosity [letter]. Clin Chem. Jun 1986;32(6):1239-40. [Medline].

  9. Jokinen CH, Swaim WR, Nuttall FQ. A case of hereditary xerocytosis diagnosed as a result of suspected hypoglycemia and observed low glycohemoglobin. J Lab Clin Med. Jul 2004;144(1):27-30. [Medline].

  10. Kagawa D, Ando S, Ueda T. [A case of chronic myelogenous leukemia with pseudohypoglycemia: correlation between leukocyte counts and blood glucose levels]. Rinsho Ketsueki. Oct 1987;28(10):1790-4. [Medline].

  11. MacDuff A, Grant IS. Facticious hypoglycaemia in hypotension. Emerg Med J. Jul 2002;19(4):376. [Medline].

  12. Nagase T, Adachi I, Yamada T, Murakami N, Morita K, Yoshino Y. Solitary fibrous tumor in the pelvic cavity with hypoglycemia: report of a case. Surg Today. 2005;35(2):181-4. [Medline].

  13. Nieman RE, Kelly JJ, Waskin HA. Severe African trypanosomiasis with spurious hypoglycemia. J Infect Dis. Feb 1989;159(2):360-2. [Medline].

  14. Petrella V, Silvera F, Massara G. [Syndrome of clinical pseudohypoglycemia]. Minerva Med. Nov 30 1984;75(45-46):2751-4. [Medline].

  15. Pink D, Schoeler D, Lindner T, Thuss-Patience PC, Kretzschmar A, Knipp H. Severe hypoglycemia caused by paraneoplastic production of IGF-II in patients with advanced gastrointestinal stromal tumors: a report of two cases. J Clin Oncol. Sep 20 2005;23(27):6809-11. [Medline].

  16. Rushakoff RJ, Lewis SB. Case of pseudohypoglycemia. Diabetes Care. Dec 2001;24(12):2157-8. [Medline].

  17. Wakami K, Tateyama H, Kawashima H, Matsuno T, Kamiya Y, Jin-No Y. Solitary fibrous tumor of the uterus producing high-molecular-weight insulin-like growth factor II and associated with hypoglycemia. Int J Gynecol Pathol. Jan 2005;24(1):79-84. [Medline].

  18. Wenk RE, Yoho S, Bengzon A. Pseudohypoglycemia with monoclonal immunoglobulin m. Arch Pathol Lab Med. Apr 2005;129(4):454-5. [Medline].

  19. Ybarra J, Isern J. Leukocytosis-induced artifactual hypoglycemia. Endocr J. Aug 2003;50(4):481-2. [Medline].

Keywords

factitious hypoglycemia, leukemic leucocytosis, glucose, artifactually low glucose concentration, glycolysis in vitro, polycythemia, leukemia, immunoglobulin M macroglobulinemia, IgM macroglobulinemia, Waldenström macroglobulinemia, pseudohypoglycemia

Contributor Information and Disclosures

Author

Robert A Gabbay, MD, PhD, Associate Professor of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Director, Penn State Diabetes Center, Hershey Medical Center, Pennsylvania State University College of Medicine
Robert A Gabbay, MD, PhD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Irina Lendel, MD, Clinical Instructor in Endocrinology, Division of Endocrinology, Diabetes, and Metabolism, Milton S Hershey Medical Center
Disclosure: Nothing to disclose.

Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences
Disclosure: Nothing to disclose.

George T Griffing, MD, Professor of Medicine, Director of General Internal Medicine, St Louis University
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Dimitris A Papanicolaou, MD, Assistant Professor, Department of Medicine/Endocrinology, Emory University
Dimitris A Papanicolaou, MD is a member of the following medical societies: American College of Physicians, Endocrine Society, and Royal Society of Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Yoram Shenker, MD, Chief of Endocrinology Section, VA Hospital of Madison, Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison
Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MD, Head, Vascular Division, Baker Medical Research Institute; Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, Director of General Internal Medicine, St Louis University
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

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