eMedicine Specialties > Endocrinology > Diabetes Mellitus

Hypoglycemia

Author: Vasudevan A Raghavan, MBBS, MD, MRCP, Assistant Professor, Department of Internal Medicine, Divisions of Endocrinology, Diabetes and Metabolism and Cardiovascular Sciences, Ohio State University; Co-director of The Ross Heart Hospital Comprehensive Lipid Management Clinic, Ohio State University Medical Center
Coauthor(s): Vellore A R Srinivasan, MSc, PhD, Associate Professor, Department of Biochemistry, Sri Balaji Vidyapeeth University, Mahatma Gandhi Medical College and Research Institute campus, Puducherry, India; Kenneth J Snow, MD, Associate Chief, Adult Diabetes, Joslin Clinic
Contributor Information and Disclosures

Updated: Aug 18, 2009

Introduction

Background

Hypoglycemia is a syndrome characterized by a reduction in plasma glucose concentration to a level that may induce symptoms of low blood sugar. Hypoglycemia typically arises from abnormalities in the mechanisms involved in glucose homeostasis. To diagnose hypoglycemia, the Whipple triad characteristically is present. This triad includes the documentation of low blood sugar, presence of symptoms, and reversal of these symptoms when the blood sugar level is restored to normal. (See image below and Image 1.)

Pathophysiology

Hypoglycemic symptoms are related to the brain and the sympathetic nervous system. Decreased levels of glucose lead to deficient cerebral glucose availability (ie, neuroglycopenia) that can manifest as confusion, difficulty with concentration, irritability, hallucinations, focal impairments (eg, hemiplegia), and eventually, coma and death. Stimulation of the sympatho-adrenal nervous system leads to sweating, palpitations, tremulousness, anxiety, and hunger.

The adrenergic symptoms often precede the neuroglycopenic symptoms and, thus, provide an early warning system for the patient. Studies have shown that the primary stimulus for the release of catecholamines is the absolute level of plasma glucose. The rate of decrease of glucose is less important. Previous blood sugar levels can influence an individual's response to a particular level of blood sugar. However, one must appreciate that a patient with chronic hypoglycemia can have almost no symptoms.

Frequency

United States

• The incidence of hypoglycemia in a population is difficult to ascertain. Patients and physicians frequently attribute symptoms (eg, anxiety, irritability, hunger) to hypoglycemia without documenting the presence of low blood sugar. The true prevalence of hypoglycemia, with blood sugar levels below 50 mg/dL, generally occurs in 5-10% of people presenting with symptoms suggestive of hypoglycemia.
  
  
  • Hypoglycemia is a known complication of several medications, and the incidence is difficult to determine with any certainty.
  • Hypoglycemia is a known complication of many therapies for diabetes; therefore, the incidence of hypoglycemia in a population of people with diabetes is very different from that in a population of people without diabetes.^1,2
  • Insulin-producing tumors are a rare but important treatable cause of hypoglycemia, with an annual incidence of 1-2 cases per million persons per year.

Mortality/Morbidity

Reactive hypoglycemia often is treated successfully with dietary changes and is associated with minimal morbidity. Mortality is not observed. Hypoglycemia occurring as a complication of therapy for diabetes is common. Mild hypoglycemia occurs in more than half of all patients with diabetes who are in therapy.

Race

No known racial predilection exists.

Sex

Reactive hypoglycemia is reported most frequently by women. Other causes of hypoglycemia are not associated with a sex predilection.

Age

Reactive hypoglycemia typically is observed in women aged 25-35 years. The average age of a patient diagnosed with an insulinoma is the early 40s, but cases have been reported in patients ranging from birth to age 80 years.³

Clinical

History

• Symptoms of hypoglycemia may be categorized as neurogenic (adrenergic) or neuroglycopenic.
  • Symptoms due to sympatho-adrenal activation include sweating, shakiness, tachycardia, anxiety, and a sensation of hunger.
  • Neuroglycopenic symptoms include weakness, tiredness, or dizziness; inappropriate behavior (sometimes mistaken for inebriation), difficulty with concentration; confusion; blurred vision; and, in extreme cases, coma and death.
  • The timing of onset of these symptoms relative to the time of meal ingestion is crucial in the evaluation of a patient with hypoglycemia. Fasting hypoglycemia typically occurs in the morning before eating or during the day, particularly in the afternoon if meals are missed or delayed. Postprandial hyperglycemia typically occurs 2-4 hours after eating food, especially when meals contain high levels of simple carbohydrates. Postprandial symptoms are typically due to reactive causes, but some patients with insulinoma also may present with postprandial symptoms. About 4-6 hours after food ingestion, plasma glucose concentrations are 80-90 mg/dL, and rates of glucose utilization and production are approximately 2 mg/kg/min. Glucose production is primarily (70-80%) from hepatic glycogenolysis, with a lesser contribution (20-25%) from hepatic gluconeogenesis.
• Reactive hypoglycemia seldom causes glucose levels to drop low enough to induce severe neuroglycopenic symptoms; therefore, a history of true loss of consciousness is highly suggestive of an etiology other than reactive hypoglycemia.
• Reactive hypoglycemia has been suggested to be more common in people who are insulin-resistant, and it may be a frequent precursor to type-2 diabetes. Therefore, patients who have a family history of type-2 diabetes or insulin-resistance syndrome (ie, hypertension, hyperlipidemia, obesity) may be at higher risk for developing hypoglycemia.
• In a study of maternal hypoglycemia, Pugh et al investigated risk factors for and results of hypoglycemia in pregnancy.⁴ Reporting on 870 obstetric patients, 436 of whom were identified as having hypoglycemia following a glucose challenge test (GCT) and the rest of whom were not hypoglycemic following a GCT, the authors found that hypoglycemia occurred more frequently in women below age 25 years and in women who had a preexisting medical condition. Hypoglycemia was less frequent in women whose prepregnancy body mass index was ³ 30. The investigators also found that patients with hypoglycemia were at greater risk of preeclampsia/eclampsia.

Physical

Physical examination usually does not yield specific findings.

Causes

• Fasting hypoglycemia
  • Nesidioblastosis is characterized by a diffuse budding of insulin-secreting cells from pancreatic duct epithelium and pancreatic microadenomas of such cells; it is a rare cause of fasting hypoglycemia in infants and an extremely rare cause in adults.
  • Causes of fasting hypoglycemia usually diagnosed in infancy or childhood include inherited liver enzyme deficiencies that restrict hepatic glucose release (deficiencies of glucose-6-phosphatase, fructose-1,6-diphosphatase, phosphorylase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, or glycogen synthetase). Inherited defects in fatty acid oxidation, including that resulting from systemic carnitine deficiency and inherited defects in ketogenesis (3-hydroxy-3-methylglutaryl-CoA lyase deficiency) cause fasting hypoglycemia by restricting the extent to which nonneural tissues can derive their energy from plasma FFA and ketones during fasting or exercise. This results in an abnormally high rate of glucose uptake by nonneural tissues under these conditions.
  • Drugs - Ethanol, haloperidol, pentamidine, quinine, salicylates, and sulfonamides
• Exogenous insulin
  • Insulin-producing tumors of pancreas: Islet cell adenoma or carcinoma (insulinoma) is an uncommon and usually curable cause of fasting hypoglycemia and is most often diagnosed in adults. It may occur as an isolated abnormality or as a component of the type I multiple endocrine neoplasia (MEN) syndrome. Carcinomas account for only 10% of insulin-secreting islet cell tumors. Hypoglycemia in patients with islet cell adenomas results from uncontrolled insulin secretion, which may be clinically determined during fasting and exercise. Approximately 60% of patients with insulinoma are female. Insulinomas are uncommon in persons younger than 20 years and are rare in those younger than 5 years. The median age at diagnosis is about 50 years, except in patients with MEN syndrome, in which it is in the mid 20s. Ten percent of patients with insulinoma are older than 70 years.
  • Non–beta-cell tumors: Hypoglycemia may also be caused by large non–insulin-secreting tumors, most commonly retroperitoneal or mediastinal malignant mesenchymal tumors. The tumor secretes abnormal insulinlike growth factor (large IGF-II), which does not bind to its plasma binding proteins. This increase in free IGF-II exerts hypoglycemia through the IGF-I or the insulin receptors. The hypoglycemia is corrected when the tumor is completely or partially removed and usually recurs when the tumor regrows.
• Autoimmune hypoglycemia - Insulin antibodies and insulin receptor antibodies
• Surreptitious sulfonylurea use/abuse
• Hormonal deficiencies - Hypoadrenalism (Cortisol), hypopituitarism (growth hormone) (in children), glucagons deficiency (rare), and epinephrine (very rare)
• Critical illnesses - Cardiac, hepatic, and renal diseases; sepsis with multiorgan failure
• Combination of one or more of the above, for example, chronic renal failure and sulphonylurea ingestion
• Reactive hypoglycemia
  • Idiopathic
  • Alimentary hypoglycemia is another form of reactive hypoglycemia that occurs in patients who have had prior upper GI surgical procedures (gastrectomy, gastrojejunostomy, vagotomy, pyloroplasty) and allows rapid glucose entry and absorption in the intestine, provoking excessive insulin response to a meal. This may occur within 1-3 hours after a meal. Very rare cases of idiopathic alimentary hypoglycemia occur in patients who have not had GI operations.
  • Congenital enzyme deficiencies - Hereditary fructose intolerance, galactosemia, and leucine sensitivity of childhood: In hereditary fructose intolerance and galactosemia, an inherited deficiency of a hepatic enzyme causes acute inhibition of hepatic glucose output when fructose or galactose is ingested. Leucine provokes an exaggerated insulin secretory response to a meal and reactive hypoglycemia in patients with leucine sensitivity of childhood.

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