Approach
The diagnosis of clinically significant hypoglycemia in adults is made when serum glucose concentration is low (<60 mg/dL) and either sympathoadrenal or neuroglycopenic symptoms are present. This is confirmed by establishing the Whipple triad, which consists of hypoglycemic symptoms, accompanying low-serum glucose concentration, and resolution of symptoms after raising the serum glucose concentration to normal.[13][18] Glucose levels below normal range indicate either failure to regulate insulin levels, excessive circulating insulin-like compound, a failure of counter-regulatory mechanisms, lack of enzymes needed for glucose production, lack of substrate required for gluconeogenesis, or severe derangement of function of organs required for glucose production, for example, liver, kidney.
Clinical presentation
The patient presenting with hypoglycemia should be able to describe either:
Sympathoadrenal symptoms:
Sweating
Anxiety
Nausea
Tremor
Hunger
Generalized tingling
Palpitations.
Or neuroglycopenic symptoms:
Blurred vision
Dizziness
Confusion
Dysarthria
Somnolence
Seizures
Focal neurologic deficits also possible.
There need not be a progression from sympathoadrenal symptoms to neuroglycopenia. The temporal relationship between symptom's onset and diet, meal time, or medication administration should be elicited. The timing of symptoms of hypoglycemia in relationship to a meal or its occurrence during a fasting state may offer clues as to the presence of certain disorders. If the symptoms occur after the patient begins a new medication or is known to take an insulin secretagogue, such as a sulfonylurea, then iatrogenic cause is strongly suspected. Symptoms occurring while the patient is in a fasting state suggest an insulinoma, insulin-like growth factor (IGF)-II hypersecretion, or a disturbance of the hypothalamic-pituitary axis or its target organs. Symptoms occurring soon after a meal raise the possibility of islet cell hypertrophy or nesidioblastosis.
Late reactive hypoglycemia can occur within 3-5 hours after a meal in some patients with prediabetes or impaired glucose tolerance, and during pregnancy.
Hypoglycemia at presentation, initial testing
If the patient is exhibiting symptoms of hypoglycemia on presentation, or at any point of the evaluation, the serum or plasma glucose concentration should be assessed promptly. Serum and plasma glucose measurements are for practical purposes equivalent, but glucometers are inaccurate below normal range, so laboratory evaluation is necessary.[37]
If blood sugar is <50 mg/dL, additional tests should immediately be collected, including serum insulin, C-peptide, proinsulin, ethanol, beta-hydroxybutyrate, liver and kidney function tests, and levels of insulin secretagogues (sulfonylureas). In a patient with chronic low energy, unexplained weight changes, hyperpigmentation, or other suspicion of pituitary or other endocrine dysfunction, consideration should also be given to assess serum cortisol, human growth hormone (HGH), thyroid-stimulating hormone, and adrenocorticotropic hormone (ACTH) levels.
No hypoglycemia at presentation, inpatient fast
In the presence of hypoglycemic symptoms but with a blood glucose concentration >50 mg/dL, the patient might not have clinically significant hypoglycemia. If symptoms are mild and nonspecific, further investigation may be deferred until the presence of hypoglycemia is confirmed by additional blood sugar readings, or if the symptoms are very typical or severe, the patient may be admitted for a 48- to 72-hour fast.
There has been some debate as to whether a 48-hour fast under observation is adequate in rendering a diagnosis, and the full 72-hour fast under observation has been found to identify individuals with an insulinoma not identified by 48-hour fast.[38] During the fast, the patient may drink noncaloric and caffeine-free beverages and is encouraged to be active. Blood glucose levels are checked every 6 hours. Once the blood sugar concentration by a finger stick is <60 mg/dL, blood glucose levels should be checked every hour, along with serum proinsulin, C-peptide, and insulin levels. The test ends upon any of the following occurrences: onset of sympathoadrenal or neuroglycopenic symptoms, blood glucose levels <50 mg/dL, or conclusion of full 72 hours under observation of fasting.
In the event of hypoglycemic symptoms accompanied by a blood glucose concentration <50 mg/dL, the following additional tests should be performed: serum sulfonylurea and beta-hydroxybutyrate, cortisol, HGH, and ACTH levels. Next, the patient is given glucagon 1 mg intramuscularly. Glucose level is checked 30 minutes later and the patient is then allowed to eat.[39]
An oral glucose tolerance test should be performed to rule out diabetes mellitus, as late reactive hypoglycemia occurring within 3-5 hours after a meal can occur in some patients with prediabetes or impaired glucose tolerance and during pregnancy.
No hypoglycemia at presentation, insulin suppression test
Alternatively, an insulin suppression test may be done. Insulin 0.4 to 0.6 unit/kg is administered intravenously after an overnight fast. Blood sugar is assessed with a finger stick every 5 minutes. The blood glucose concentration should decline to <60 mg/dL within 15 to 25 minutes. At this time and in 5-minute intervals for 3 additional times, blood is drawn for serum glucose, C-peptide, cortisol, and HGH levels. The patient is given 50 mL of 50% dextrose intravenously to aid in recovery at the end of the test.
Further testing for elevated C-peptide
Inappropriate elevation of C-peptide, proinsulin, and insulin suggest either insulinoma or sulfonylurea use.[34]
These results should lead to serum sulfonylurea testing, and if that is negative, imaging to detect an insulinoma.
Imaging begins with computed tomography (CT) of the abdomen and pelvis, with and without intravenous contrast. If this fails to detect a suspected insulinoma, transabdominal ultrasound is employed, and if that also fails to locate the insulinoma, endoscopic ultrasound may be used. Octreotide nuclear scanning may be employed if the suspected insulinoma still has not been localized.[40]
Further testing for low C-peptide
A low beta-hydroxybutyrate and a rapid rise >25 mg/dL in serum glucose within 30 minutes of glucagon administration suggest the presence of excessive exogenous insulin or IGF-II.
Low C-peptide, proinsulin, and insulin levels suggest excess IGF-II, which should lead to imaging to detect mesenchymal tumor. Characteristics following 72-hour fast: low insulin level, low beta-hydroxybutyrate, a >25 mg/dL increase in glucose in response to glucagons, and elevated serum IGF-II levels.
Imaging begins with CT of the abdomen and pelvis, with and without intravenous contrast. As the tumors are generally large when they cause clinically significant hypoglycemia, they may also be detectable on physical exam.
Insulin levels are high but both proinsulin and C-peptide levels are low in the case of surreptitious insulin injection.
Serum insulin antibodies will confirm surreptitious insulin injection as the cause of hypoglycemia.
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