AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

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. 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.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

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.

DIFFERENTIALS

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Other Problems to be Considered

Simulating hypoglycemia
Transient ischemic attacks
Cardiac dysrhythmia
Pheochromocytoma
Substance abuse, eg, cocaine

WORKUP

Section 5 of 11  

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• Follow-up
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Lab Studies

• During hypoglycemic episodes, patients should test their glucose at home to document hypoglycemia that is occurring with the episodes. Take into consideration that meter readings may not be accurate enough to establish the diagnosis.
• Test glucose and insulin levels simultaneously to document low glucose levels occurring in conjunction with inappropriate insulin levels.
• Administer an oral glucose tolerance test if reactive hypoglycemia is suspected. An oral glucose tolerance test provides little benefit for the evaluation of fasting hypoglycemia. Perform the test for 5 hours while simultaneously testing glucose and insulin levels. To be meaningful, low blood sugar during the test should be accompanied by typical symptoms. Response to a mixed meal may be more representative.
• A supervised fast is the most reliable diagnostic test for the evaluation of fasting hypoglycemia. Continue the fast for as long as 72 hours or until symptoms develop in the presence of hypoglycemia (blood sugar <45 mg/dL for women, <55 mg/dL for men). Obtain simultaneous insulin levels every 6 hours, when glucose is low and when symptoms develop. Glucose and/or glucagon must be administered after blood sample withdrawal to abort hypoglycemic symptoms.
• Obtain C-peptide levels any time an elevated insulin level is obtained. Endogenous hyperinsulinemia from insulinoma is associated with elevated C-peptide concentrations with concurrent hypoglycemia. Exogenous hyperinsulinemia from injected insulin results in low concentrations of C-peptide, both because of the effect of the associated hypoglycemia and because of the direct suppressive effect of insulin on the pancreatic beta cell.
• Other causes of hypoglycemia should be properly investigated. For example, a morning cortisol level determination and/or adrenocorticotropic hormone (ACTH) stimulation testing should be performed if adrenal insufficiency is suspected. 
• Remember that whole blood glucose values may be spuriously low in polycythemia rubra vera because of the unequal distribution of glucose between erythrocytes and plasma, excessive glycolysis by erythrocytes, or both. Low blood glucose values in leukemia are due to excessive glycolysis by leukocytes and in hemolytic crisis from excessive glycolysis by nucleated erythrocytes. In the polycythemic patient or in serum of the leukemic or hemolytic patient, prompt measurement of glucose in plasma to which an antiglycolytic agent has been added should provide accurate results.

Imaging Studies

• For the evaluation of insulinomas, CT scan and ultrasound often are not helpful because most of these tumors are small. MRI may be better.
• Selective arteriography often is helpful.
• Selective percutaneous transhepatic venous sampling often is helpful for localizing an insulinoma to the head, body, or tail of the pancreas.
• Octreotide scanning localizes insulinomas in approximately half the cases.
• Intraoperative ultrasound can be used as a diagnostic aid.
• Retroperitoneal tumors that are producing insulin-like growth factor (IGF) usually are imaged easily using a CT scan.

Other Tests

• Proinsulin normally represents less than 20% of total immunoreactive insulin. In patients with islet-cell tumors, proinsulin may contribute as much as 70% of insulin immunoreactivity.
• Provocative tests involving the administration of arginine, leucine, calcium, glucagon, or tolbutamide generally are of limited value because their sensitivity or specificity is inadequate.
• Diagnostic algorithm: A systematic approach is often required to establish the true cause of hypoglycemia, using an algorithmic approach. One such algorithm is given below (see Image 1).

TREATMENT

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Medical Care

If dietary therapy is inadequate, medical care for patients with fasting hypoglycemia may include intravenous (IV) glucose infusion. However, IV octreotide is effective for suppressing endogenous insulin secretion. Reactive hypoglycemia does not require medical care.

Surgical Care

Definitive treatment for fasting hypoglycemia caused by a tumor is surgical resection. The success rate is good for benign islet-cell adenomas, and the success rate for malignant islet-cell tumors can be as high as 50%.

Diet

• Dietary therapy may be effective for improving symptoms in patients with fasting hypoglycemia. Frequent meals/snacks are preferred, especially at night, with complex carbohydrates.
• For patients with reactive hypoglycemia, initiate a carbohydrate restriction. Patients should avoid simple sugars, increase the frequency of their meals, and reduce the size of their meals. Patients may require 6 small meals and 2-3 snacks per day.

Activity

Because exercise burns carbohydrates and increases sensitivity to insulin, patients with fasting hypoglycemia should avoid significant activity. On the other hand, patients with reactive hypoglycemia often find that their symptoms improve after embarking on a routine exercise program.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Inhibitors of insulin secretion

These drugs increase glucose levels by reducing peripheral glucose metabolism.

Drug Category: Antineoplastic agents

These agents inhibit cell growth and proliferation.

FOLLOW-UP

Section 8 of 11  

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• Follow-up
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Further Outpatient Care

• If the patient has fasting hypoglycemia and the cause is treatable, long-term follow-up usually is not needed. If the cause cannot be treated definitively (eg, inoperable pancreatic insulinoma), diazoxide can be used to elevate blood glucose levels and chemotherapy that specifically targets the beta cell (ie, using cytotoxic agents such as streptozotocin) should be considered.
• If the patient has reactive hypoglycemia, periodic outpatient monitoring is warranted to assess the continued presence of symptoms.

Complications

• Untreated fasting hypoglycemia can lead to severe neuroglycopenia and, possibly, death.
• Untreated reactive hypoglycemia may cause significant discomfort to the patient, but long-term sequelae are not likely.

Prognosis

• Prognosis depends on the cause of the hypoglycemia. If the cause of fasting hypoglycemia is identified and curable, prognosis is excellent. If the problem is not curable, such as an inoperable malignant tumor, long-term prognosis is poor. However, note that these tumors may progress rather slowly.
• If the patient has reactive hypoglycemia, symptoms often spontaneously improve over time, and long-term prognosis is very good.

Patient Education

For excellent patient education resources, visit eMedicine's Diabetes Center. Also, see eMedicine's patient education article, Low Blood Sugar.

MISCELLANEOUS

Section 9 of 11  

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• Introduction
• Clinical
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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to identify the presence of fasting hypoglycemia rather than postprandial hypoglycemia
• Failure to evaluate fasting hypoglycemia with a prolonged fast (ie, as long as 72 h)
• Failure to document true hypoglycemia as a cause of symptoms

MULTIMEDIA

Section 10 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Diagnostic algorithm. A systematic approach is often required to establish the true cause of hypoglycemia, using an algorithmic approach.
	View Full Size Image
Media type:  Chart

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• Follow-up
• Miscellaneous
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• References

• Cryer PE, Polonsky KS. Glucose homeostasis and hypoglycemia. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams Textbook of Endocrinology. 9^th ed. Philadelphia, Pa: WB Saunders; 1998:939-71.
• Field JB. Hypoglycemia. Definition, clinical presentations, classification, and laboratory tests. Endocrinol Metab Clin North Am. Mar 1989;18(1):27-43. [Medline].
• Ibarra JD Jr. Hypoglycemia. Postgrad Med. Feb 1972;51(2):88-93. [Medline].
• Koch B. Selected topics of hypoglycemia care. Can Fam Physician. Apr 2006;52:466-71. [Medline].
• Service FJ. Classification of hypoglycemic disorders. Endocrinol Metab Clin North Am. Sep 1999;28(3):501-17, vi. [Medline].
• Service FJ. Diagnostic approach to adults with hypoglycemic disorders. Endocrinol Metab Clin North Am. Sep 1999;28(3):519-32, vi. [Medline].
• Service FJ. Hypoglycemia. Endocrinol Metab Clin North Am. Dec 1997;26(4):937-55. [Medline].
• Service FJ. Hypoglycemic disorders. N Engl J Med. Apr 27 1995;332(17):1144-52. [Medline].
• Shamoon H. Hypoglycemia. In: Endocrinology and Metabolism. 3^rd ed. New York, NY: McGraw-Hill; 1995:1251-69.

Article Last Updated: Sep 26, 2007