From the Guidelines
The workup for unexplained hypoglycemia should begin with a thorough history and physical examination, followed by laboratory testing during a hypoglycemic episode, with the goal of identifying the underlying cause and preventing future episodes, as recommended by the most recent guidelines 1. The critical test is Whipple's triad: documented low blood glucose (<55 mg/dL), symptoms of hypoglycemia, and resolution of symptoms with glucose administration. During a hypoglycemic episode, obtain a "critical sample" including plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, sulfonylurea screen, and antibodies to insulin. Some key points to consider in the workup include:
- Identifying the underlying cause of hypoglycemia, such as exogenous causes (medication effects, particularly insulin or sulfonylureas), endogenous hyperinsulinism (insulinoma, nesidioblastosis), non-islet cell tumors, critical illness, hormone deficiencies (adrenal insufficiency, growth hormone deficiency), or metabolic disorders (glycogen storage diseases, fatty acid oxidation disorders) 1.
- Using validated tools to assess awareness of hypoglycemia, such as the Clarke score, Gold score, or Pedersen-Bjergaard score 1.
- Considering the classification of hypoglycemia, with level 1 hypoglycemia defined as a measurable glucose concentration <70 mg/dL (3.9 mmol/L) but ≥54 mg/dL (3.0 mmol/L), level 2 hypoglycemia defined as a blood glucose concentration <54 mg/dL (3.0 mmol/L), and level 3 hypoglycemia defined as a severe episode requiring assistance from another person 1. Additional testing should include comprehensive metabolic panel, thyroid function tests, cortisol levels, and growth hormone levels to rule out endocrine disorders. Imaging studies such as abdominal CT or MRI may be necessary if insulinoma is suspected. A 72-hour supervised fast remains the gold standard diagnostic test for suspected endogenous hyperinsulinism, during which blood samples are collected at regular intervals and when glucose levels drop below 55 mg/dL. For patients with reactive hypoglycemia, a mixed-meal tolerance test may be more appropriate. The workup aims to differentiate between various causes of hypoglycemia and to guide treatment, with the goal of preventing future episodes and improving quality of life, as emphasized in the recent guidelines 1.
From the Research
Evaluation of Unexplained Hypoglycemia
The evaluation of unexplained hypoglycemia involves a systematic approach to identify the underlying cause. According to 2, the evaluation should start by documenting Whipple's triad, which includes symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised.
Clinical Clues to Potential Hypoglycemic Etiologies
The next step is to pursue clinical clues to potential hypoglycemic etiologies, such as:
- Drugs
- Critical illnesses
- Hormone deficiencies
- Nonislet cell tumors In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism 2.
Laboratory Tests
In patients suspected of having endogenous hyperinsulinism, laboratory tests should be performed to measure:
- Plasma glucose
- Insulin
- C-peptide
- Proinsulin
- Beta-hydroxybutyrate
- Circulating oral hypoglycemic agents during an episode of hypoglycemia 2. Additionally, insulin antibodies should be measured.
Role of Glucagon and Catecholamines
Glucagon plays a primary counterregulatory role in preventing hypoglycemia during fasting 3. Sympathochromaffin catecholamines, such as adrenomedullary epinephrine, become critical when glucagon is deficient. Other hormones, neurotransmitters, or substrate effects may also be involved, but they appear to stand low in the hierarchy of glucoregulatory factors 3.
Insulin and C-peptide Levels
In sulfonylurea-induced hypoglycemia, insulin and C-peptide levels can be elevated, even after hypoglycemic therapy 4. Insulin levels >3.9 muIU/mL and C-peptide levels >1.4 ng/mL are consistent with sulfonylurea-induced hypoglycemia. However, these levels can be lower before hypoglycemic therapy, but still consistent with sulfonylurea-induced hypoglycemia 4.
Key Points to Consider
Some key points to consider in the workup of unexplained hypoglycemia include:
- Documenting Whipple's triad
- Pursuing clinical clues to potential hypoglycemic etiologies
- Measuring plasma glucose, insulin, C-peptide, and other laboratory tests during an episode of hypoglycemia
- Considering the role of glucagon and catecholamines in preventing hypoglycemia
- Evaluating insulin and C-peptide levels in sulfonylurea-induced hypoglycemia These points can help guide the evaluation and management of unexplained hypoglycemia, as discussed in 5, 6, and 2.