> Table of Contents > Hypoglycemia, Nondiabetic
Hypoglycemia, Nondiabetic
Matthew A. Silva, PharmD, RPh, BCPS
Pablo I. Hernandez Itriago, MD, MS, FAAFP
image BASICS
DESCRIPTION
  • Hypoglycemia defined by the Whipple triad
    • Low plasma glucose level (≤60 mg/dL) with hypoglycemic symptoms that are relieved when glucose is corrected.
    • Occurs commonly in patients with diabetes receiving sulfonylurea or insulins; less commonly in patients without diabetes
  • Reactive hypoglycemia occurs in response to a meal, drugs, herbal substances, or nutrients and may occur 2 to 3 hours postprandially or later (1).
    • Symptoms are generally observed with serum glucose ≤60 mg/dL, lower in patients with hypoglycemic unawareness.
    • Also seen after GI surgery (in association with dumping syndrome in some patients)
  • Spontaneous (fasting) hypoglycemia may be associated with primary conditions including hypopituitarism, Addison disease, myxedema, or disorders related to hepatic dysfunction or renal failure (1,2).
    • If hypoglycemia presents as a primary disorder, consider hyperinsulinism and extrapancreatic tumors.
EPIDEMIOLOGY
Incidence
  • True incidence is unknown.
  • 0.5-8.6% of hospitalized patients ≥65 years (3,4,5)
    • Asymptomatic in 25% of cases
Prevalence
True prevalence is unknown:
  • Predominant age: older adult
  • Predominant sex: female > male
ETIOLOGY AND PATHOPHYSIOLOGY
  • Reactive, postprandial
    • Alimentary hyperinsulinism
    • Meals high in refined carbohydrate
    • Certain nutrients, including fructose, galactose, leucine
    • Glucose intolerance (prediabetes)
    • GI surgery
    • Idiopathic (unknown cause)
  • Spontaneous
    • Fasting
    • Alcohol or prescription medication-associated (6) (insulin, sulfonylureas, thiazolidinediones, incretin mimetics, DPP-IV inhibitors, &bgr;-blockers, salicylates, quinine, hydroxychloroquine, fluoroquinones, doxycycline, sertraline, disopyramide, pentamidine)
    • Nonprescription over-the-counter (OTC) agents, including performance-enhancing agents. Adulterated versions of phosphodiesterase inhibitors and performance-enhancing agents are routinely imported and may contain sulfonylureas and other hypoglycemic agents.
    • Consider medication errors as a source of unexplained hypoglycemia even in patients without diabetes.
    • Surreptitious drug use (self-injection of insulin or ingestion of oral hypoglycemic medications in patients with diabetes)
    • Natural medicines or herbs (bitter melon, caffeine, cassia cinnamon, chromium, fenugreek, ginseng, guarana, mate, stevia, vanadium)
    • Postsurgical (e.g., gastrectomy, Roux-en-Y) hypoglycemia/dumping syndrome
    • Islet cell hyperplasia or tumor (insulinoma)
    • Extrapancreatic insulin-secreting tumor
    • Hepatic disease
    • Glucagon deficiency
    • Adrenal insufficiency
    • Catecholamine deficiency
    • Hypopituitarism
    • Hypothyroidism
    • Eating disorders
    • Exercise
    • Fever
    • Pregnancy
    • Renal glycosuria
    • Large tumors
    • Ketotic hypoglycemia of childhood
    • Enzyme deficiencies or defects
    • Severe malnutrition
    • Sepsis
    • Total parenteral nutrition therapy
    • Hemodialysis
Genetics
Some aspects may involve genetics (e.g., hereditary fructose intolerance).
RISK FACTORS
Refer to “Etiology and Pathophysiology.”
GENERAL PREVENTION
  • Follow dietary and exercise guidelines.
  • Patient recognition of early symptoms and knowledge of corrective action
Pediatric Considerations
  • Usually divided into two syndromes
    • Transient neonatal hypoglycemia
    • Hypoglycemia of infancy and childhood
  • Screening infants for hypoglycemia is appropriate when pregnancy was complicated by maternal diabetes.
  • Cases of hypoglycemia observed in children taking propranolol for infantile hemangioma
  • Associated with indomethacin when treating patent ductus arteriosus
Geriatric Considerations
  • More likely to have underlying disorders or be caused by medications
  • Iatrogenic hypoglycemia is common in the hospitalized elderly with renal insufficiency.
COMMONLY ASSOCIATED CONDITIONS
  • Severe liver disease; alcoholism
  • Addison disease; adrenocortical insufficiency
  • Myxedema
  • Malnutrition (patients with renal failure)
  • GI surgery
  • Panhypopituitarism
  • Insulinoma
image DIAGNOSIS
PHYSICAL EXAM
  • CNS (neuroglycopenic) symptoms predominate with gradual glucose reduction:
    • Convulsions
    • Coma
    • Hypotension
  • Adrenergic symptoms: more prominent in acute drop in glucose
    • Tremulousness
    • Diaphoresis
    • Warmth/flushing
    • Heart palpitations
DIFFERENTIAL DIAGNOSIS
CNS disorders
  • Psychogenic
  • Pseudohypoglycemia: Symptoms of hypoglycemia or self-diagnosis in patients in whom low blood glucose may not be detectable and may be impossible to convince that they do not suffer from hypoglycemia after all tests are found to be normal.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Blood glucose ≤45 mg/dL (≤2.5 mmol/L) when symptomatic followed by symptom resolution with feeding (2)[C]
  • Plasma glucose overnight fasting: ≤60 mg/dL (≤3.33 mmol/L); confirm on ≥2 occasions (2)[C].
  • Plasma glucose 72-hour fasting:
    ≤45 mg/dL (≤2.5 mmol/L) for females; ≤55 mg/dL (≤3.05 mmol/L) for males; fasting may be ended when Whipple triad is achieved or hypoglycemia is demonstrated (2)[C].
  • Abdominal CT to rule out abdominal tumor
Follow-Up Tests & Special Considerations
  • Misinterpretation of glucose tolerance tests may lead to misdiagnosis of hypoglycemia; ≥1/3 of normal patients have hypoglycemia, with or without symptoms, during the 4-hour glucose tolerance test. These patients may be at future risk for type 2 diabetes.
  • C-peptide measurement (2)[C]
  • Check liver studies, serum insulin, adrenocorticotrophic hormone (ACTH), and cortisol. Serum insulin should be suppressed when glucose is <60 mg/dL.
  • Serum &bgr;-hydroxybutyrate (2)[C]
  • Insulin radioimmunoassay: Elevated insulin levels suggest islet cell hyperplasia or tumor.
  • Drugs that may alter lab results: Many drugs can affect glucose levels; refer to drug or laboratory reference.
P.531

Diagnostic Procedures/Other
  • For definitive diagnosis, patient should have
    • Documented low glucose levels
    • Symptoms when glucose levels are low
    • Evidence that symptoms are relieved specifically by ingestion of sugar or other food
    • Identification of the specific type of hypoglycemia
  • Serum &bgr;-hydroxybutyrate <2.7 mg/dL in the presence of high serum insulin, C-peptide, and low serum glucose suggests excessive insulin production (2)[C].
image TREATMENT
GENERAL MEASURES
  • Outpatient except for severe cases; may also be inpatient for testing
  • Oral carbohydrate for alert patient without drug overdose (2 to 3 tbsp of sugar in glass of water or fruit juice, 1 to 2 cups of milk, piece of fruit, or several soda crackers)
  • If unable to swallow: Use glucagon IM or SC.
  • If caused by medication or nutrients: Avoid or control causative agents.
  • If triggered by meals: Try high-protein diet with carbohydrate restriction.
  • Nonhypoglycemic hypoglycemia or pseudohypoglycemia
    • Many patients (often women aged 20 to 45 years) present with diagnosis of reactive hypoglycemia (self-diagnosed or misinterpretation of tests).
    • Symptoms may pertain to chronic fatigue and somatic complaints (stress often plays a role in these symptoms).
    • Management difficult; listening is important. Try 120-g carbohydrate diet.
    • Counseling may be useful for stress and other problems.
MEDICATION
  • Once diagnosis is established, begin therapy appropriate for underlying disorder.
  • If unable to swallow: glucagon 1 mg (1 unit) IM or SC. If no response, give IV bolus of 25 to 50 g of 50% glucose solution followed by continuous infusion until patient able to take by mouth.
  • Postsurgical gastrectomy patients unresponsive to dietary changes may benefit from propantheline, psyllium, fiber, or oat bran, which delays gastric emptying.
  • Insulinoma
SURGERY/OTHER PROCEDURES
If islet cell tumor (insulinoma) or other insulin-secreting tumor, surgery is treatment of choice; if inoperable, diazoxide may relieve symptoms (1)[C].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Hypoglycemia unresponsive to oral intake
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Exercise routine or daily activity may need to be reevaluated.
  • Patients with recurrent hypoglycemia should have glucose source at hand for immediate ingestion during symptoms.
Patient Monitoring
  • Depends on type and severity of symptoms and treatment of underlying cause
  • Hypoglycemia from sulfonylureas can last for hours to days depending on half-life and renal function.
DIET
  • High protein, high fiber, complex carbohydrates from multigrain, and whole foods in moderation
  • Frequent small feedings (six daily)
  • Avoid fasting.
PATIENT EDUCATION
  • Dietary instruction
  • Counseling for stress, if appropriate
  • Recognition of early symptoms of hypoglycemia and how to take corrective action
PROGNOSIS
Favorable, with appropriate treatment
REFERENCES
1. Guettier JM, Gorden P. Hypoglycemia. Endocrinol Metab Clin North Am. 2006;35(4):753-766.
2. Service FJ. Hypoglycemic disorders. N Engl J Med. 1995;332(17):1144-1152.
3. Kagansky N, Levy S, Rimon E, et al. Hypoglycemia as a predictor of mortality in hospitalized elderly patients. Arch Intern Med. 2003;163(15):1825-1829.
4. Mannucci E, Monami M, Mannucci M, et al. Incidence and prognostic significance of hypoglycemia in hospitalized non-diabetic elderly patients. Aging Clin Exp Res. 2006;18(5):446-451.
5. Nirantharakumar K, Marshall T, Hodson J, et al. Hypoglycemia in non-diabetic in-patients: clinical or criminal? PLoS One. 2012;7(7):e40384.
6. Ben Salem C, Fathallah N, Hmouda H, et al. Drug-induced hypoglycaemia: an update. Drug Saf. 2011;34(1):21-45.
Additional Reading
&NA;
  • Bharmal SV, Moyes V, Ahmed S, et al. Hypoglycaemia: possible mediation by chromium salt medication. Hormones (Athens). 2010;9(2):181-183.
  • Cansu DU, Korkmaz C. Hypoglycaemia induced by hydroxychloroquine in a non-diabetic patient treated for RA. Rheumatology (Oxford). 2008;47(3): 378-379.
  • Chan TY. Outbreaks of severe hypoglycaemia due to illegal sexual enhancement products containing undeclared glibenclamide. Pharmacoepidemiol Drug Saf. 2009;18(12):1250-1251.
  • Lawrence KR, Adra M, Keir C. Hypoglycemiainduced anoxic brain injury possibly associated with levofloxacin. J Infect. 2006;52(6):e177-e180.
  • Pollak PT, Mukherjee SD, Fraser AD. Sertralineinduced hypoglycemia. Ann Pharmacother. 2001;35(11):1371-1374.
  • Singh M, Jacob JJ, Kapoor R, et al. Fatal hypoglycemia with levofloxacin use in an elderly patient in the post-operative period. Langenbecks Arch Surg. 2008;393(2):235-238.
  • Yamada C, Nagashima K, Takahashi A, et al. Gatifloxacin acutely stimulates insulin secretion and chronically suppresses insulin biosynthesis. Eur J Pharmacol. 2006;553(1-3):67-72.
See Also
&NA;
  • Hypoglycemia, Diabetic; Insulinoma
  • Algorithm: Hypoglycemia
Codes
&NA;
ICD10
  • E16.2 Hypoglycemia, unspecified
  • E16.1 Other hypoglycemia
  • P70.4 Other neonatal hypoglycemia
Clinical Pearls
&NA;
  • Symptoms coincide with low blood glucose levels and resolve with PO/IV glucose or glucagon.
  • Avoid known agents/nutrients that trigger hypoglycemia.
  • Treat underlying cause.