Hypoglycemia in Adults

Background

• Hypoglycemia in persons without diabetes is a clinical syndrome defined as plasma glucose low enough to cause autonomic and/or neuroglycopenic signs or symptoms including impaired brain function. It is documented by Whipple triad (presence of low plasma glucose concentration, characteristic symptoms and/or signs, and symptom resolution when plasma glucose is normalized).
• Hypoglycemia occurs infrequently in patients without medication-treated diabetes but may occur in:
  • seemingly well patients, including those with insulinoma, postgastric bypass hypoglycemia, insulin autoimmunity, and factitious hypoglycemia
  • patients with concurrent illness, including those with critical illnesses, hormone deficiencies such as cortisol and growth hormone, and nonislet cell tumors
  • patients taking a medication or toxin that causes hypoglycemia, including insulin, insulin secretagogue, or alcohol
• Hypoglycemia is usually episodic, typically occur during fasting, exercise, or the postprandial period and characterized by nonspecific symptoms including:
  • autonomic symptoms (a physiological counter regulatory mechanism responsible for awareness of hypoglycemia) such as palpitations, tremor, anxiety, and sweating that result from epinephrine secretion
  • neuroglycopenic symptoms (due to central nervous system glucose deprivation) such as behavior or mental status changes, fatigue, weakness, and seizures that result from brain glucose deprivation

Evaluation

• Diagnose hypoglycemia and evaluate for a hypoglycemic disorder only in patients with low plasma glucose concentration, characteristic symptoms and/or signs, and symptom resolution when plasma glucose is normalized (documented Whipple triad) (Strong recommendation).
• In seemingly well patients in whom the cause of hypoglycemia is not immediately evident, use the following evaluation strategy (Strong recommendation) to distinguish between endogenous hyperinsulinism and accidental, surreptitious, or malicious hypoglycemia.
  • During an episode of spontaneous hypoglycemia:
    • Before administering glucagon, measure plasma levels of glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and oral hypoglycemic agents (especially sulfonylureas and glinides) .
    • Observe plasma glucose response to IV injection of 1 mg glucagon.
  • If a spontaneous hypoglycemic episode cannot be observed (Whipple triad not documented):
    • Recreate the circumstances in which symptomatic hypoglycemia is likely to occur, such as during a fast of up to 72 hours or after a mixed meal (one the patient already associates with producing symptoms). Do not perform an oral glucose tolerance test.
      • The fast can begin at home the previous night and completed in an outpatient clinical setting, which may eliminate the need for hospitalization for full 72-hour fast
      • Endogenous hyperinsulinism is indicated by symptoms and/or signs of hypoglycemia together with:
        • glucose < 55 mg/dL (3 mmol/L)
        • insulin ≥ 3 microunits/mL (18 pmol/L)
        • C-peptide ≥ 0.6 ng/mL (0.2 nmol/L)
        • proinsulin ≥ 5 pmol/L
        • beta-hydroxybutyrate ≤ 2.7 mmol/L
      • Endogenous hyperinsulinism (or mediation by an insulin-like growth factor [IGF]) may also be documented by administering glucagon 1 mg IV at the end of the fast and:
        • observing beta-hydroxybutyrate ≤ 2.7 mmol/L
        • documenting an increase in plasma glucose of at least 25 mg/dL (1.4 mmol/L) at 10, 20, and 30 minutes
        • providing the patient with a high-carbohydrate meal, as glucagon effects will wear off and hypoglycemia may recur
    • Consider measuring plasma cortisol, growth hormone, IGF-II, and pro-IGF-II if relevant history is present and if insulin level is suppressed.
  • Evaluation for insulinoma
    • Suspect insulinoma in patients with documented fasting or postprandial endogenous hyperinsulinemic hypoglycemia, negative screening for oral hypoglycemic agents, response to glucagon, and no circulating antibodies against insulin.
    • Insulin levels are often > 160 microunits/mL within 15-30 minutes after intramuscular or IV glucagon administration in patients with insulinomas, though some patients do not hypersecrete insulin after glucagon injection.
    • Testing options for localizing insulinoma include:
      • computed tomography (CT) or magnetic resonance imaging (MRI)
      • transabdominal and endoscopic ultrasound
      • selective pancreatic arterial calcium injections with measurements of hepatic venous insulin levels, if prior imaging is inconclusive
    • Diagnosis of insulinoma is typically confirmed with positive imaging studies; if no tumor is found on imaging, consider selective pancreatic arterial calcium injective (SPACI) testing or Gallium-68 somatostatin receptor scintigraphy.
  • If hyperinsulinemic hypoglycemia is confirmed, measure insulin (and insulin receptor) antibodies to evaluate for insulin autoimmune hypoglycemia.
• Additional testing to define the cause of hypoglycemia may include:
  • SPACI testing to determine the extent of pancreatic beta cell hyperfunction
  • genetic testing for patients with insulinomas if concern for multiple endocrine neoplasia type 1 (MEN1) and for patients with noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
• Characteristic clinical findings will usually identify patients with critical illness as the cause of hypoglycemia; consider further evaluation for suspected critical illness as appropriate, including:
  • evaluation for adrenal insufficiency if serum cortisol is low
  • For additional information on diagnostic testing for other critical illnesses, see:
    • Acute Liver Failure or Cirrhosis of the Liver
    • Acute Kidney Injury in Adults or Overview of Chronic Kidney Disease (CKD) in Adults
    • Heart Failure With Reduced Ejection Fraction (HFrEF)
    • Sepsis in Adults or Sepsis in Children (including that caused by Malaria)

Management

• Acute management of hypoglycemia after completion of planned testing (including evaluation for response to glucagon) or once diagnosis is established
  • Route of treatment depends on clinical status of patient.
  • In patients with advanced neuroglycopenic symptoms who cannot take oral glucose:
    • Give initial dose of dextrose 25 g IV followed by continuous infusion of 5%-10% dextrose.
    • Alternative treatment, if no IV access, is glucagon.
      • Suggested dose is 1 mg intramuscularly or subcutaneous injection.
      • May repeat dose if there is no response within 15 minutes; if patient does not respond, administer IV dextrose. If patient does not have insulin-mediated hypoglycemia, hypoglycemia will not respond to glucagon.
      • Glucagon should be followed by an alternate glucose source (food or IV dextrose) as the effects will wear off.
  • In patients who are awake and willing, glucose 15-20 g orally is the preferred initial treatment, repeated every 15 minutes as needed to maintain euglycemia.
  • Monitor plasma glucose frequently during treatment. Initially, monitor every 15 minutes until the patient is euglycemic.
    • If etiology is medication overdose, the pharmacokinetics of the ingested medication will dictate the need for further monitoring; for example, hours for intermediate-release glipizide and potentially days if on glyburide with renal failure.
    • If etiology is consistent with insulinoma, aggressive dietary counseling and medication management may allow for relatively expedient discharge.
• Management by cause of hypoglycemia
  • Insulinoma
    • Surgical resection of a benign insulinoma is curative.
    • If resection is not possible, other treatment options for benign insulinomas include:
      • diazoxide or octreotide (alone or in combination)
      • local-regional ablative therapies such as transcutaneous or laparoscopic radiofrequency ablation, high-intensity focused ultrasound ablation (HIFU), ultrasound-assisted alcoholization, or selective chemoembolization
      • glucocorticoids in patients with refractory hypoglycemia
    • In patients with malignant insulinoma (reported in < 10% of cases):
      • Palliative surgery to remove or debulk the primary tumor is generally suggested, but depends on tumor location and extension into surrounding tissues.
      • Metastatic disease
        • Distant metastases are usually localized to the liver and regional lymph nodes.
        • Pancreas and liver resection can sometimes be performed during the same operation; lymph node dissection should also be performed if there is evidence of nodal disease.
        • Consider resection of liver metastases, especially when metastatic disease is confined to the liver and surgery can remove > 90% of tumor.
        • Other approaches for management of liver disease include hepatic artery embolization, transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), radiofrequency ablation, cryoablation, and liver transplantation in selected patients with unresectable liver metastases.
      • Pharmacological therapy options include pasireotide, long-acting somatostatin analogs and peptide radionuclide therapy, and mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus.
    • For additional treatment information, see Insulinoma.
  • Bariatric surgery
    • Treatment options for postgastric bypass hypoglycemia include dietary modifications (such as balanced meals limiting refined carbohydrates), medical and surgical treatment depending on severity of hypoglycemia and response.
      • The initial intervention is dietary modifications to prevent glucose surge after meals.
      • For patients who do not respond to dietary treatment, consider additional medical treatment while continuing modified diet; options include:
        • acarbose
        • diazoxide
        • somatostatin analogs
        • calcium channel blockers
        • GLP-1 receptor agonists
      • Some patients may require a combination of medical treatments.
      • For patients who do not respond to dietary modifications and for whom all medical treatment options have been exhausted, consider surgical intervention; options include:
        • reversal of gastric bypass
        • placement of feeding tube in the remnant stomach
        • gastric banding to slow gastric emptying
    • For additional treatment information, see Treatment section of Post-gastric Bypass Hypoglycemia.
  • Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
    • The treatment decision for NIPHS should balance the risks of therapy and degree of debilitation caused by hypoglycemic spells.
    • A commonly used strategy is to begin with dietary counseling and medication management first, and if they fail to then consider surgical treatment if debilitating symptoms persist.
    • Medical therapy options include dietary modifications, including low-carbohydrate diet with frequent feedings and medications such as acarbose, diazoxide, octreotide or other somatostatin analogs, or calcium channel blockers such as verapamil or nifedipine.
      • Uncooked cornstarch to provide a slow release carbohydrate source may be required.
      • Calcium channel blockers have limited evidence for efficacy.
    • If medical treatment is not successful and symptoms are debilitating, consider partial pancreatectomy.
  • Autoimmune hyperinsulinemic hypoglycemia
    • Autoimmune hyperinsulinemic hypoglycemia due to insulin autoantibodies, which primarily occurs among persons of Japanese descent, is often self-limiting; treatment usually involves corticosteroids or other immunosuppressants.
    • Type B insulin resistance syndrome
      • Treatment should aim to correct hypoglycemia and target the autoimmune response.
      • Treatment options for glycemic control include dietary modifications and high-dose corticosteroids.
      • Rituximab may be considered for immunomodulation in patients with recurrent hypoglycemia.
  • Drugs or underlying illness
    • Discontinue or reduce dose of offending drug.
    • Treat underlying illness.
      • Cortisol deficiency (adrenal insufficiency) should be treated with glucocorticoid replacement and repletion of other adrenal hormones as needed.
        • In adults with suspected adrenal crisis, immediately give hydrocortisone 100 mg IV followed by appropriate fluid resuscitation and hydrocortisone 200 mg/day as a continuous infusion or 6 hourly injections for 24 hours (Strong recommendation).
        • In children with suspected adrenal crisis, give immediate hydrocortisone 50 mg/m² parenterally, followed by appropriate fluid resuscitation and hydrocortisone 50-100 mg/m²/day by continuous IV or in divided doses every 6 hours (Strong recommendation).
      • Growth hormone (GH) deficiency should be treated with recombinant human GH replacement therapy; see Growth Hormone Deficiency in Adults and Growth Hormone Deficiency in Children for additional treatment information.
      • Nonislet cell tumor
        • Treatment goals should be immediate correction of hypoglycemia, followed by treatment directed at the underlying tumor, and prevention of recurrent hypoglycemia if the tumor cannot be cured.
        • If tumor is incurable, reduction in mass by surgery, radiotherapy, and/or chemotherapy may alleviate hypoglycemia.
        • Medications to consider for incurable nonislet cell tumors include glucocorticoids, growth hormone, long-acting glucagon, and octreotide in some patients.