Pseudohypoglycemia

Pseudohypoglycemia is an event when a person experiences typical symptoms of hypoglycemia but with a measured plasma glucose concentration above 70 mg/dL (>3.9 mmol/L). ^{[1, 2]} The term was used in the past to describe the disparity between actual and measured plasma/capillary glucose.

The term clinical pseudohypoglycemia is used when patients with personality and 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. ^{[3, 4]}  Pseudohypoglycemic symptoms in the absence of a decline in glucose levels have been associated with psychosomatic disorders, emotion dysregulation, and sleep disturbance. ^[5]

It is important for clinicians to recognize the difference between true and pseudohypoglycemia to prevent unnecessary investigations or excessive treatment.

Pseudohypoglycemia or artifactual hypoglycemia can occur in the following situations:

• Decreased capillary flow resulting in decreased glucose transport through the tissues and increased tissue extraction of glucose. ^[6] It can occur in the following conditions:

  • Raynaud phenomena ^{[7, 8]}

  • Acrocyanosis ^[9]

  • Peripheral vascular disease

  • Eisenmenger syndrome ^[10]

  • Circulatory shock

• Increased glycolysis by the leucocytes and red blood cells when there is a delay in interpreting the blood sample or separating plasma from the blood sample. Even in patients with normal leucocyte counts an artificial decrease in glucose level (0.17 mmol/L/h) is seen when it is allowed to clot at room temperature. ^[11] Serum glucose concentration starts falling precipitously within 2 hours of collection if not refrigerated. ^[12] A 90% lowering of glucose levels occurred when the blood was kept at room temperature for 2 hours. That can happen with the following:

  • Leukemia ^{[13, 14, 15]}

  • Leukemoid reactions including eosinophilic leukemoid reaction due to underlying poorly differentiated carcinoma and hematopoietic cytokines-stimulated leukocytosis. ^[11]

  • Polycythemia vera ^{[12, 16]}

  • The same findings have also been observed in blood samples containing high levels of other cell types due to the above mechanism as in chronic hemolytic anemia. ^{[17, 18]} Primary red cell disorders associated with decreased survival and reticulocytosis can also alter glycohemoglobin measurement making it appear low. ^[18]

  • African trypanosomiasis causes in vitro use of glucose. ^[19]

• Hyperviscosity syndromes can cause artifactual hypoglycemia as well, as observed in the following:

  • Waldenstrom macroglobulinemia ^{[20, 21]}

  • Monoclonal gammaglobulinemia of undetermined significance (MGUS) ^[22]

  • This is no longer observed after the plasmapheresis or appropriate dilution of the sample to a serum viscosity of 1.4-1.8, as measured with a capillary Ostwald viscometer ^{[20, 21, 22]}

  • Hypertriglyceridemia ^[23]

• Effect of various drugs on interpretation of glucose by different glucose meters. ^[24] Although there is a dose response relationship with the drug level and glucose interpretation, this is confounded by various factors especially in critically ill patients due to associated liver or kidney dysfunction, which may raise the level of the drugs even when given at a therapeutic dose. It becomes clinically important to monitor these patients closely. Drugs causing that problem include the following:

  • Ascorbic acid (especially high doses used in cancer therapy) ^{[25, 26]}

  • Dopamine

  • Acetaminophen

  • Mannitol

• In hospital settings, various other factors should be taken into consideration which may affect the glucose meter readings. Severe acidosis (pH < 6.95) can falsely decrease glucose readings. ^[23]  Patients receiving high flow oxygen can have false low readings with a glucose meter using the glucose oxidase method. ^[23]  High hematocrit, as in neonates, can also cause false low blood glucose readings. ^[27]

Venous plasma glucose concentrations greater than 70 mg/dL (3.9 mmol/L) after an overnight fast are within reference ranges. As per American Diabetes Association (ADA) guidelines, hypoglycemia is considered if plasma glucose is less than 70 mg/dL (3.9 mmol/L). ^{[1, 2, 28]} However, in some groups of patients, such as young females, values of 50-70 mg/dL (2.8-3.9 mmol/L) may be normal. ^[29]

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.

Evaluating concurrent blood count as well as other parameters such as protein level is important to evaluate the cause of falsely low glucose levels.

Since the discovery of insulin in 1924, hypoglycemic symptoms have been reported in nondiabetic patients. It was thought to result from dysinsulinism. ^[30] In 1975, Yager and Young described a syndrome of nonhypoglycemia in which patients presented with varied spectrum of symptoms that they attributed to low glucose. ^[31]

In 1961, Fields and Williams used the term artifactual hypoglycemia to describe the falsely low glucose that occurred in patients with chronic myelogenous leukemia. ^[32]

The terms pseudohypoglycemia and artifactual hypoglycemia have been used since then to describe this symptomatology.

Although the patients may be asymptomatic, they may be subjected to unnecessary testing based on the abnormal laboratory result. Occasionally, patients may present with nonspecific symptoms such as fatigue, headache, visual disturbances, and lightheadedness.

Clinical correlation becomes of utmost importance in such circumstances. Some patients may present with typical symptoms of neuroglycopenia such as slurred speech, confusion, and, rarely, seizures and coma, in which case further workup is required.

The clinical diagnosis of hypoglycemia is established when symptoms are consistent with hypoglycemia, a low plasma glucose concentration is confirmed, and symptoms subside in the presence of normal plasma glucose levels after treatment (Whipple's triad).

Absence of symptoms with low glucose values should raise the suspicion of artifactual hypoglycemia. The following actions are recommended in an effort to prevent it:

• Seeing the patient as a whole and keeping in mind other comorbid conditions that might interfere with the glucose reading as described above

• Evaluation of potential drugs that might interfere with the testing

• Confirmation of glucose measurement in capillary blood or in venous blood collected in tubes with antiglycolytic agents such as sodium fluoride

• Prompt serum separation and refrigeration of blood samples