Pseudohypoglycemia 

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 leukocytosis, polycythemia, or both. It may occur when the separation of plasma from the formed elements of the blood is delayed.

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.^{[1, 2]}

Pseudohypoglycemia has been observed in the following conditions:

• Leukemias (eg, chronic lymphocytic leukemia) and leukemoid reaction (eg, eosinophilic leukemoid reaction due to an underlying, poorly differentiated carcinoma)^{[3, 4]}
• Benign forms of leukocytosis (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)^[5]
• Chronic hemolytic anemia in hemolytic crisis, accompanied by a high count of nucleated red blood cells (the abnormality was reversed with a decrease of nucleated red blood cell count to 3%)^[6]
• 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)
• 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)^{[7, 8]}
• African trypanosomiasis, which is caused by in vitro utilization of glucose by the parasites^[9]
• Hypovolemic shock and Raynaud phenomenon (finger-stick glucose testing has been observed; venous glucose levels were normal in both settings)

El Khoury et al suggested that pseudohypoglycemia may occur in cases of impaired microcirculation when low capillary flow and increased glucose transit time promote increased glucose extraction by the tissue. In addition, they concluded that indications of hypoglycemia in the presence of impaired microcirculation should raise suspicions of pseudohypoglycemia.^[10]

In the El Khoury et al study, the authors reported on a patient with Raynaud phenomenon who displayed symptoms of hypoglycemia along with Raynaud-associated color changes in the hands.^[10] Although glucose levels obtained from multiple finger-stick capillary glucose tests ranged from 32-45 mg/dL, concurrent plasma glucose levels were 1.5-2 times higher. After the differences between the patient’s capillary and venous glucose levels were confirmed using capillary glucose tests on the arms and legs, pseudohypoglycemia was diagnosed.

Primary red cell disorders associated with decreased red blood cell survival and reticulocytosis may alter glycohemoglobin measurements, making them appear low.^[11]

Prevention

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

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

• Leukocytosis^[12]
• Polycythemia
• Delay in the separation of plasma from formed blood elements
• Chronic anemia in a hemolytic crisis
• Trypanosomiasis

Low glucose concentration results from the metabolism of glucose in vitro by the large number of leukocytes 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 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/hr, 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]).

Occasionally, neoplasms may cause episodes of true hypoglycemia by the following^{[13, 14, 15]} :

• Releasing insulinlike compounds, as described for mesotheliomas of the retroperitoneal space, fibromas, and mesenchymal tumors
• Rapid metabolism of glucose by large numbers of leukemic cells
• Trapping of insulin by monoclonal IgG immunoglobulins in multiple myeloma
• A deficiency in liver glucose-6-phosphatase or extensive liver involvement

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.