Hypoglycemia Workup

Updated: Feb 13, 2023
  • Author: Osama Hamdy, MD, PhD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Approach Considerations

Search for a source of infection. Studies should be considered to rule out the possibility of a concurrent occult infection contributing to the new hypoglycemic episode (eg, complete physical examination, chest radiography (particularly in diabetic patients presenting with hypoglycemia), urinalysis, blood cultures).

Check liver function tests, serum insulin levels, and cortisol and thyroid levels. Proinsulin normally represents less than 20% of total immunoreactive insulin; in patients with islet-cell tumors, proinsulin may contribute as much as 70% of insulin immunoreactivity.

Provocative tests involving the administration of arginine, leucine, calcium, glucagon, or tolbutamide are generally of limited value, because their sensitivity or specificity is inadequate. [22]

Other causes of hypoglycemia should be properly investigated (see Differentials). For example, a morning cortisol level determination and/or adrenocorticotropic hormone (ACTH) stimulation testing should be performed if adrenal insufficiency is suspected.

See a diagnostic algorithm for hypoglycemia below.

Diagnostic algorithm. A systematic approach is oft Diagnostic algorithm. A systematic approach is often required to establish the true cause of hypoglycemia, using an algorithmic approach.

Glucose and Insulin Levels

During hypoglycemic episodes, patients should test their glucose at home to document hypoglycemia that is occurring with the episodes. Take into consideration that meter readings may not be accurate enough to establish the diagnosis.

Test glucose and insulin levels simultaneously to document low glucose levels occurring in conjunction with inappropriate insulin levels.

Keep in mind that whole blood glucose values may be spuriously low in polycythemia rubra vera because of the unequal distribution of glucose between erythrocytes and plasma, excessive glycolysis by erythrocytes, or both. Low blood glucose values in leukemia are due to excessive glycolysis by leukocytes and in hemolytic crisis from excessive glycolysis by nucleated erythrocytes. In the polycythemic patient or in serum of the leukemic or hemolytic patient, prompt measurement of glucose in plasma to which an antiglycolytic agent has been added should provide accurate results.

A study by Craig and McLaughlin suggested that in patients with established post–bariatric surgery hypoglycemia, a blood glucose level below 54 mg/dL should indicate clinically important hypoglycemia. The investigators based this on the peak occurring in neuroglycopenic (NG) symptoms at glucose levels of < 54-40 mg/dL during provoked and real-world hypoglycemia, “the low sensitivity/high specificity of NG symptoms to detect hypoglycemia, and high prevalence of hypoglycemia unawareness at glucose values < 54 mg/dL.” [23]

Oral glucose tolerance test

Administer an oral glucose tolerance test if reactive hypoglycemia is suspected. An oral glucose tolerance test provides little benefit for the evaluation of fasting hypoglycemia. Perform the test for 5 hours while simultaneously testing glucose and insulin levels. To be meaningful, low blood sugar (< 50 mg/dL [< 2.78 mmol/L]) during the test should be accompanied by typical symptoms. Response to a mixed meal may be more representative.

72-Hour fasting plasma glucose

A supervised fast is the most reliable diagnostic test for the evaluation of fasting hypoglycemia. Continue the fast for as long as 72 hours or until symptoms develop in the presence of hypoglycemia (blood sugar < 45 mg/dL (2.5 mmol/L) for women; < 55 mg/dL (3.05 mmol/L) for men). Obtain simultaneous insulin levels every 6 hours, when glucose is low and when symptoms develop. Also measure the beta-hydroxybutyrate serum level. Glucose and/or glucagon must be administered after blood sample withdrawal to abort hypoglycemic symptoms. The diagnosis of insulinoma is likely if the patient, at the conclusion of the fast, has neuroglycopenic symptoms, a fall in plasma glucose to less than 45 mg/dL (< 2.5 mmol/L), inappropriately elevated beta-cell polypeptides (insulin, proinsulin, and C-peptide levels), and a beta-hydroxybutyrate level of less than 2.7 mmol/L.

For overnight fasting plasma glucose levels, symptoms of hypoglycemia may develop when the blood sugar is below 60 mg/dL (3.33 mmol/L).


C-Peptide Levels

Obtain C-peptide levels any time an elevated insulin level is obtained. Endogenous hyperinsulinemia from insulinoma is associated with elevated C-peptide concentrations with concurrent hypoglycemia. Exogenous hyperinsulinemia from injected insulin results in low concentrations of C-peptide, both because of the effect of the associated hypoglycemia and because of the direct suppressive effect of insulin on the pancreatic beta cell. [17]

C-peptide levels are elevated in insulinoma, normal or low with exogenous insulin, and elevated with oral sulfonylureas.


Radiologic Studies

For the evaluation of insulinomas, computed tomography (CT) scanning and ultrasonography often are not helpful, because most of these tumors are small. Magnetic resonance imaging (MRI) may yield better results.

Selective percutaneous transhepatic venous sampling often is helpful for localizing an insulinoma to the head, body, or tail of the pancreas, and selective arteriography is also often helpful in localizing insulin-secreting lesions. Octreotide scanning localizes insulinomas in approximately 50% of cases.

Retroperitoneal tumors that are producing insulinlike growth factor (IGF) are usually imaged easily using a CT scan.