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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 is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, and Endocrine Society

Coauthor(s): 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

Editors: Dimitris A Papanicolaou, MD, Assistant Professor, Department of Medicine/Endocrinology, Emory University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; 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; Mark Cooper, MD, Head, Vascular Division, Baker Medical Research Institute; Professor of Medicine, Monash University; George T Griffing, MD, Professor of Medicine, Director of General Internal Medicine, St Louis University

Author and Editor Disclosure

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

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.



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



Hypoglycemia


Lab 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.



Deterrence/Prevention

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



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.



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Pseudohypoglycemia excerpt

Article Last Updated: Sep 21, 2007