Practice Essentials

Hypoglycemia is characterized by a reduction in plasma glucose concentration to a level that may induce
symptoms or signs such as altered mental status and/or sympathetic nervous system stimulation. This
condition typically arises from abnormalities in the mechanisms involved in glucose homeostasis. The
most common cause of hypoglycemia in patients with diabetes is injecting a shot of insulin and skipping
a meal or overdosing insulin.

The image below depicts a diagnostic algorithm for hypoglycemia.

Signs and symptoms

The glucose level at which an individual becomes symptomatic is highly variable (threshold generally at <
50 mg/dL). Carefully review the patient's medication and drug history for potential causes of
hypoglycemia (eg, new medications, insulin usage or ingestion of an oral hypoglycemic agent, possible
toxic ingestion).

The patient’s medical and/or social history may reveal the following:

Diabetes mellitus, renal insufficiency/failure, alcoholism, hepatic cirrhosis/failure, other endocrine

diseases, or recent surgery

Central nervous system: Headache, confusion, personality changes

Ethanol intake and nutritional deficiency

Weight reduction, nausea and vomiting

Fatigue, somnolence

Neurogenic or neuroglycopenic symptoms of hypoglycemia may be categorized as follows:

Neurogenic (adrenergic) (sympathoadrenal activation) symptoms: Sweating, shakiness, tachycardia,

anxiety, and a sensation of hunger

Neuroglycopenic symptoms: Weakness, tiredness, or dizziness; inappropriate behavior (sometimes

mistaken for inebriation), difficulty with concentration; confusion; blurred vision; and, in extreme cases,
coma and death

Reactive hypoglycemic include the following features:

More common in overweight and obese people who are insulin-resistant

May be a frequent precursor to type 2 diabetes

Possible higher risk in patients with a family history of type 2 diabetes or insulin-resistance syndrome

True loss of consciousness is highly suggestive of an etiology other than reactive hypoglycemia.

Gestational hypoglycemia may have the following features [1] :

More frequent in women younger than 25 years

More frequent in women with a preexisting medical condition

Less frequent in women whose prepregnancy body mass index was ≥30 kg/m2

Greater risk of preeclampsia/eclampsia in affected women

See Clinical Presentation for more detail.

Diagnosis

Rapid diagnosis and treatment is essential in any patient with suspected hypoglycemia, regardless of the
cause. The Whipple triad is characteristically present: documentation of low blood sugar, presence of
symptoms, and reversal of these symptoms when the blood glucose level is restored to normal.

Physical findings, however, are nonspecific in hypoglycemia and are generally related to the central and
autonomic nervous systems. Examination includes the following:

Vital signs

Head, eyes, ears, nose, and throat

Cardiovascular

Neurologic

Pulmonary

Gastrointestinal

Dermatologic

Elderly persons exhibit fewer symptoms of hypoglycemia, and their threshold of plasma glucose is lower
at presentation than in younger persons.

Laboratory studies

Patients with no previous history of hypoglycemia require a complete workup to find a potentially
treatable disease. Laboratory studies that should be obtained include the following:
Glucose and electrolyte levels (including calcium, magnesium)

Oral glucose tolerance test and/or 72-hour fasting plasma glucose

Complete blood count

Other tests that may be helpful including the following:

Blood cultures

Urinalysis

Serum insulin, cortisol levels, and thyroid hormone levels

C-peptide levels

Proinsulin

Management

Pharmacotherapy

The mainstay of therapy for hypoglycemia is glucose. Other medications may be administered based on
the underlying cause or the accompanying symptoms.

Medications used in the treatment of hypoglycemia include the following:

Glucose supplements (eg, dextrose)

Glucose-elevating agents (eg, glucagon)

Inhibitors of insulin secretion (eg, diazoxide, octreotide)

Antineoplastic agents (eg, streptozocin)

Other therapies

Fasting hypoglycemia: Dietary therapy (frequent meals/snacks preferred, especially at night, with
complex carbohydrates); IV glucose infusion; IV octreotide

Reactive hypoglycemia: Dietary therapy (restriction of refined carbohydrates, avoidance of simple sugars,
increased meal frequency, increased protein and fiber); alpha-glucosidase inhibitors

Pathophysiology

Hypoglycemic symptoms are related to sympathetic activation and brain dysfunction secondary to
decreased levels of glucose. Stimulation of the sympathoadrenal nervous system leads to sweating,
palpitations, tremulousness, anxiety, and hunger. Reduction in cerebral glucose availability (ie,
neuroglycopenia) can manifest as confusion, difficulty with concentration, irritability, hallucinations, focal
impairments (eg, hemiplegia), and, eventually, coma and death.

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, it is important to note that a patient with repeated hypoglycemia can have almost no
symptoms (hypoglycemic unawareness). The threshold at which a patient feels the hypoglycemic
symptoms decreases with repeated episodes of hypoglycemia.

Etiology

Causes of hypoglycemia are varied, but it is seen most often in diabetic patients. Hypoglycemia may
result from medication changes or overdoses, infection, diet changes, metabolic changes over time, or
activity changes; however, no acute cause may be found. Other causes include alimentary problems,
idiopathic causes, fasting, insulinoma, endocrine problems, extrapancreatic causes, hepatic disease, post
bariatric surgery, and miscellaneous causes.

Fasting hypoglycemia

Nesidioblastosis is a rare cause of fasting hypoglycemia in infants and an extremely rare cause in adults.
This condition is characterized by a diffuse budding of insulin-secreting cells from pancreatic duct
epithelium and pancreatic microadenomas of such cells.

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
free fatty acids (FFA) and ketones during fasting or exercise. This results in an abnormally high rate of
glucose uptake by nonneural tissues under these conditions.

Several cases of nesidioblastosis were reported recently after gastric bypass surgery.

Drugs
Ethanol (including propranolol plus ethanol), haloperidol, pentamidine, quinine, salicylates, and
sulfonamides ("sulfa drugs") have been associated with hypoglycemia. Other drugs that may be related
to this condition include oral hypoglycemics, phenylbutazone, insulin, bishydroxycoumarin, p-
aminobenzoic acid, propoxyphene, stanozolol, hypoglycin, carbamate insecticide, disopyramide,
isoniazid, methanol, methotrexate, tricyclic antidepressants, cytotoxic agents, organophosphates,
didanosine, chlorpromazine, fluoxetine, sertraline, fenfluramine, trimethoprim, 6-mercaptopurine,
thiazide diuretics, thioglycolate, tremetol, ritodrine, disodium ethylenediaminetetraacetic acid (EDTA),
clofibrate, angiotensin converting enzyme (ACE) inhibitors, and lithium.

A study by Fournier and colleagues indicates that treatment for pain with the opioid analgesic tramadol
increases a patient’s risk of being hospitalized for hypoglycemia. Information from the United Kingdom
Clinical Practice Research Datalink and the Hospital Episode Statistics database was analyzed for 28,110
patients who were newly prescribed tramadol and 305,924 individuals who were newly prescribed
codeine, all for noncancer pain, with 11,019 controls also included in the study. Using case-control,
cohort, and case-crossover analysis, the investigators found that tramadol increased the risk of
hospitalization for hypoglycemia by more than three-fold, with the risk particularly elevated in the first
30 days of treatment. The actual risk was small, however, occurring in about 7 patients per 10,000
annually. [2, 3]

A study by Eriksson et al indicated that in patients with type 2 diabetes undergoing second-line
treatment, the combination of metformin and sulfonylurea carries a greater risk for severe
hypoglycemia, cardiovascular disease, and all-cause mortality than does the combination of metformin
and dipeptidyl peptidase-4 inhibitor (DPP4i). [4]

Similarly, a study by Gautier et al found that patients with type 2 diabetes treated with metformin plus
insulin secretagogues (such as sulfonylurea or glinide) were more likely to experience hypoglycemia than
were those treated with metformin plus DPP4i while starting insulin. Both groups achieved similar
glycemic control. [5]

Surreptitious sulfonylurea use/abuse

Factitious hypoglycemia or self-induced hypoglycemia can be seen in healthcare workers or in relatives

who care for diabetic family members at home. (see Type 1 Diabetes Mellitus and Type 2 Diabetes
Mellitus for further discussion, including the diagnostic use of C-peptide levels and hemoglobin A1C).

Exogenous insulin

Surreptitious use of insulin may be seen, typically among those likely to have access to insulin.
Measurement of insulin level along with C-peptide is very crucial in making this diagnosis.

Endogenous insulin or insulin-receptor–mediated hypoglycemia

Sources of endogenous insulin include insulin-producing tumors of pancreas and non–beta-cell tumors.

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 multiple endocrine neoplasia type I (MEN I) 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 the median age is in
the mid third decade of life. 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.

Reactive hypoglycemia

Reactive hypoglycemia can be idiopathic, due to alimentary problems, or a result of congenital enzyme
deficiencies.

Alimentary hypoglycemia is another form of reactive hypoglycemia that occurs in patients who have had
previous upper gastrointestinal (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 include 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.

Other causes of hypoglycemia include the following, singly or in combination (eg, chronic renal failure
and sulfonylurea ingestion):
Autoimmune hypoglycemia: Insulin antibodies and insulin receptor antibodies

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

Exercise (in patients with diabetes treated with diabetes medications)

Pregnancy

Renal glycosuria

Ketotic hypoglycemia of childhood

Adrenal insufficiency

Hypopituitarism

Starvation

Artifact