Hypoglycemia
Hypoglycemia
Hypoglycemia
Hypoglycemia is a condition that occurs when the sugar levels in your blood are too low. Many people
think of hypoglycemia as something that only occurs in people with diabetes. However, it can also occur in
people who don’t have diabetes.
Hypoglycemia is different from hyperglycemia, which occurs when you have too much sugar in your
bloodstream. Hypoglycemia can happen in people with diabetes if the body produces too much insulin.
Insulin is a hormone that breaks down sugar so that you can use it for energy. You can also get
hypoglycemia if you have diabetes and you take too much insulin.
If you don’t have diabetes, hypoglycemia can happen if your body can’t stabilize your blood sugar levels. It
can also happen after meals if your body produces too much insulin. Hypoglycemia in people who don’t
have diabetes is less common than hypoglycemia that occurs in people who have diabetes or related
conditions.
Here's what you need to know about hypoglycemia that occurs without diabetes.
Reactive hypoglycemia
Reactive hypoglycemia occurs within a few hours after a meal. An overproduction of insulin causes reactive
hypoglycemia. Having reactive hypoglycemia may mean that you’re at risk for developing diabetes.
Non-reactive hypoglycemia
Non-reactive hypoglycemia isn't necessarily related to meals and may be due to an underlying disease.
Causes of non-reactive, or fasting, hypoglycemia can include:
some medications, like those used in adults and children with kidney failure
excess amounts of alcohol, which can stop your liver from producing glucose
any disorder that affects the liver, heart, or kidneys
some eating disorders, such as anorexia
pregnancy
Although it's rare, a tumor of the pancreas can cause the body to make too much insulin or an insulin-like
substance, resulting in hypoglycemia. Hormone deficiencies can also cause hypoglycemia because
hormones control glucose levels.
Dumping syndrome
If you’ve had surgery on your stomach to alleviate the symptoms of gastroesophageal reflux disease, you
may be at risk for a condition known as dumping syndrome. In late dumping syndrome, the body releases
excess insulin in response to carbohydrate-rich meals. That can result in hypoglycemia and the related
symptoms.
Carry a snack
Always carry a snack with you. You can eat it to prevent hypoglycemia from happening. It's best to carry a
quick source of carbohydrates to boost your blood sugar levels. Protein will help keep sugar in your system
for a longer period as your body absorbs it.
Hypoglycemia in Pregnancy
Glucose is the main source of energy for your body. Hypoglycemia is characterized by abnormal low
levels of blood sugar or blood glucose. Hypoglycemia often occurs with diabetes treatment.
However, nondiabetics can suffer from it due to a variety of medical ailments. Hypoglycemia is not a
disease in itself, but an indicator of some underlying disease. Hypoglycemia in pregnancy is quite
common, but should not be ignored.
1. With Diabetes
Type 1 or type 2 diabetics may take insulin to lower high blood sugar levels which could lead to
hypoglycemia. Besides, taking too much insulin, consuming less glucose or exercising excessively
may lead to hypoglycemia in pregnancy.
2. Without Diabetes
Hypoglycemia is very often during early months of pregnancy. This occurs due to metabolic changes
occurring as a result of loss of gluconeogenic substances (byproducts of digestion of protein) and
glucose to the growing fetus, which leads to low glucose levels in the mother.
Medicines: Accidentally taking someone else’s drugs for diabetes is a possible cause. Medications
like quinine used to treat malaria may cause hypoglycemia in children or in patients suffering
from kidney failure
Drinking alcohol excessively without eating
Critical illnesses such as severe hepatitis
A rare tumor of pancreas leading to insulin overproduction
Hormonal deficiencies due to disorders of the pituitary or the adrenal glands
Hypoglycemia may sometimes occur after having a meal due to overproduction of insulin,
referred to as postprandial or reactive hypoglycemia
2. Hormonal Injection
Alternatively, a female may be prescribed a glucagon kit to use at home as the injection of this
hormone can increase the level of blood sugar, which stimulates the liver to produce more sugar
and send it into the blood.
3. Emergency Treatment
You can self-treat most of the episodes of hypoglycemia. However, in severe cases where one is
unable to drink or eat, it may become necessary to seek emergency treatment. If a female becomes
unconscious due to hypoglycemia, do not put anything into her mouth and call 911. In case you or
someone else in the family is trained to inject glucagon and if it’s available you can inject it.
Having pre-diabetes or being at risk for diabetes, which can lead to trouble making the
Reactive right amount of insulin
hypoglycemia Stomach surgery, which can make food pass too quickly into your small intestine
Rare enzyme deficiencies that make it hard for your body to break down food
Medicines, such as
o salicylates (a type of pain reliever)
o sulfa drugs (an antibiotic)
o pentamidine (to treat a serious kind of pneumonia)
o quinine (to treat malaria)
Alcohol, especially with binge drinking
Serious illnesses, such as those affecting the liver, heart, or kidneys
Low levels of certain hormones, such as cortisol, growth hormone, glucagon, or
Fasting epinephrine
hypoglycemia Tumors, such as a tumor in the pancreas that makes insulin or a tumor that makes a
similar hormone called IGF-II
ABSTRACT
Hypoglycemia (glucose <55 mg/dL) is uncommon in people without diabetes. Whipple’s triad (low plasma
glucose concentration, clinical signs/symptoms consistent with hypoglycemia, and resolution of signs or
symptoms when the plasma glucose concentration increases) should be documented in patients prior to
embarking on evaluation. Medications should be reviewed. Critical illnesses, malnutrition, hormone
deficiencies especially adrenal insufficiency, and nonislet cell tumors secreting IGF-II need be considered in
those who are ill. Hypoglycemia can also follow bariatric surgery. In apparently healthy individuals,
endogenous hyperinsulinism due to insulinoma, functional β-cell disorders, or insulin autoimmune
conditions are possible, as are accidental, surreptitious or factitious causes of hypoglycemia. Tests
performed during hypoglycemia can establish the cause in those whom illness or medications are not the
cause. Testing may be done at the time of spontaneous development of symptoms. If this is not possible, it
can be done in the setting of a prolonged supervised fast or during a mixed meal test. Endogenous
hyperinsulinism is supported by insulin ≥3 uU/mL, c-peptide ≥0.2 nmol/L, proinsulin ≥5 pmol/L, beta-
hydroxybutyrate ≤2.7 mmol/L and undetectable sulfonylurea/meglitinide in the setting of hypoglycemia.
Use of glucagon tolerance tests, c-peptide suppression tests, anti-insulin antibody testing and continuous
glucose monitoring are discussed. Treatment of hypoglycemia is tailored to the etiology. Accurate diagnosis
is needed to direct medical and/or surgical treatment for non-diabetic hypoglycemia. For complete coverage
of this and all related areas of Endocrinology, please visit our FREE on-line web-
textbook, www.endotext.org.
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INTRODUCTION
Hypoglycemia is uncommon in people who are not being treated for diabetes, and may be due to varied or
multiple etiologies. Different causes of hypoglycemia should be considered in patients who are apparently
healthy compared to those who are ill. Whipple’s triad (low plasma glucose concentration, clinical signs or
symptoms consistent with hypoglycemia, and resolution of signs or symptoms when the plasma glucose
concentration increases) should be documented prior to embarking on evaluation (1-3). Appropriate blood
tests performed at the time of hypoglycemia can establish the etiology in those for whom illness or
medications are not a readily apparent cause. Testing should be done at the time of spontaneous
development of symptoms when feasible. If this is not possible, testing can be done in the setting of a
prolonged supervised fast or during a mixed meal test as described in this review. Additional diagnostic tests
are also discussed. Treatment of hypoglycemia should be tailored to its cause and may include dietary,
medical and/or surgical therapies.
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PHYSIOLOGY
Glucose is the solitary source of energy for the brain under normal conditions (4). In order to maintain
proper brain function, plasma glucose must be maintained within a relatively narrow range. Redundant
counter-regulatory mechanisms are in place to prevent or correct hypoglycemia. As glucose levels decline,
major defense mechanisms include a decrease in insulin secretion, an increase in glucagon secretion, and an
increase in epinephrine secretion. Increased cortisol and growth hormone secretion occur in prolonged
hypoglycemia. If these defenses fail and plasma glucose levels continue to fall then symptoms prompting
food ingestion will develop. Symptoms typically develop at a plasma glucose of 55 mg/dl (3.0 mmol/liter) in
otherwise healthy individuals (5-6). At glucose levels of 55 mg/dl (3.0 mmol/l) and lower, insulin secretion
is normally almost completely suppressed. Lower plasma glucose levels occur in healthy individuals without
symptoms or signs during extended fasting when there is use of alternative fuels such as ketones (1).
Because of this variability there is not a single plasma glucose concentration that defines hypoglycemia. In
type 1 and longstanding type 2 diabetes the counter-regulatory responses to hypoglycemia are frequently
impaired and shift to lower thresholds (1,7-8), but have not been as well studied in patients with chronic
hypoglycemia in the absence of diabetes..
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Neurogenic Neuroglycopenic
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DIFFERENTIAL DIAGNOSIS
In individuals with hypoglycemia in the absence of diabetes mellitus the differential diagnosis is broad
(Table 2). Multiple etiologies may be present concurrently. Different causes of hypoglycemia should be
considered in patients who are apparently healthy compared to those who are ill. Drugs, critical illnesses,
hormone deficiencies, and nonislet cell tumors should be considered in those who are ill or taking
medications. In apparently healthy individuals, endogenous hyperinsulinism due to insulinoma, functional β-
cell disorders, or insulin autoimmune conditions are possible, as are accidental, surreptitious or factitious
causes of hypoglycemia. Hypoglycemia in patients who have had bariatric surgery is increasingly
recognized as the frequency of these operations has grown. Artifactual hypoglycemia can occur if blood
samples are improperly handled (lack of antiglycolytic agent in the collection tube) and there is a delay in
processing.
Drugs are the most common cause of hypoglycemia (Table 3) (1). Drug-induced hypoglycemia is more
common in older patients with underlying comorbidities and in those taking glucose lowering medications
(14-16). Hypoglycemia in the setting of critical illness is not unusual. Sepsis, hepatic, renal or cardiac failure
and hormone deficiencies (cortisol, glucagon and epinephrine) are other causes of hypoglycemia. Non-islet
cell tumors and endogenous hyperinsulinism (such as insulinoma, noninsulinoma pancreatogenous
hypoglycemia, and autoimmune hypoglycemia) are rare causes of hypoglycemia (1). Accidental,
surreptitious or malicious hypoglycemia due to administration of insulin or insulin secretagogues need also
to be considered.
Insulinomas primarily cause hypoglycemia in the fasting state, but may cause symptoms in the postprandial
period as well. The incidence is 1/250,000 patient-years. Less that 10% are malignant, multiple or present in
patients with multiple endocrine neoplasia type 1 (MEN-1) syndrome (1).
Noninsulinoma pancreatogenous hypoglycemia typically causes hypoglycemia in the postprandial state.
These patients have diffuse islet involvement with nesidioblastosis (islet hypertrophy, hyperplasia and
enlarged and hyperchromatic β-cell nuclei) (17). Some patients who have had bariatric surgery for the
treatment of obesity, most commonly Roux-en-Y gastric bypass surgery, will develop hypoglycemia. This
may be due to pancreatic islet nesidioblastosis, a preexisting insulinoma, or may be due to reactive
hypoglycemia related to abnormal transport of food to the small intestine or abnormal secretion of other
glucoregulatory hormones (18-24). The incidence of hypoglycemia following Roux-en-Y gastric bypass
surgery is unknown.
Antibodies to insulin or the insulin receptor are rare causes of hypoglycemia (1,13). Antibodies to native
insulin occur primarily in patients of Japanese and Korean descent (25). Patients with autoimmune
hypoglycemia may have other autoimmune disease or exposure to sulfhydryl containing drugs (26). Late
postprandial hypoglycemia occurs as insulin secreted in response to the meal disassociates from antibodies
(1). Diagnosis is made with documentation of elevated insulin antibody levels in the absence of exposure to
exogenous insulin.
DIAGNOSTIC TESTS
The most recent clinical practice guidelines for the evaluation and management of adult hypoglycemic
disorders were published by the Endocrine Society in 2009 (1). The testing approach is also discussed in the
Endotext chapter on pancreatic-islet function testing (27).
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Initial Evaluation
Evaluation should be conducted in patients in whom Whipple’s triad (low plasma glucose concentration,
clinical signs or symptoms consistent with hypoglycemia, and resolution of signs or symptoms when the
plasma glucose concentration increases) is documented. Patients with hypoglycemia typically present with a
history of “spells” concerning for hypoglycemia, or have an incidental low plasma glucose measurement.
The first step is to review the patient’s history in detail, including type of symptoms, timing of episodes, and
relation to food ingestion, comorbid conditions, medications and social history.
Consideration for hormone deficiencies and nonislet cell tumors should be given. When adrenal
insufficiency is considered, a Cortrosyn stimulation test should be performed. If the cause of hypoglycemia
is not apparent then further laboratory testing is indicated. Capillary blood glucose measurements should not
be used in the diagnosis of hypoglycemic disorders due to their poor accuracy in these situations.
If possible, testing should be done during a time of symptomatic hypoglycemia. Simultaneous measurements
of plasma glucose, insulin, c-peptide, proinsulin, and beta-hydroxybutyrate and a screen for oral
hypoglycemic agents (sulfonylureas and meglitinide) should be performed (Table 4). Glucagon, 1 mg IV,
should then be administered with careful follow up of the glucose response every 10 minutes for 30 minutes.
These tests distinguish between hypoglycemia due to hyperinsulinism (endogenous and exogenous) and
other causes.
If testing cannot be performed during a spontaneous episode of hypoglycemia, either a fast of up to 72 hours
or a mixed meal test done in a monitored setting followed by administration of glucagon is the most useful
diagnostic strategy as described below. The choice of test is based on the circumstances in which
hypoglycemia is most likely to occur.
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Table 4
Distinguishing Causes of Symptomatic Hypoglycemia [glucose < 55 mg/dl (3.0 mmol/l)] After a
Prolonged Fast
a
Insulinoma, noninsulinoma pancreatogenous hypoglycemia (NIPHS), post gastric bypass hypoglycemia.
Adapted from: Cryer, PE, et al. Evaluation and Management of Adult Hypoglycemic Disorders: An
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709-728, 2009
Approximately 75% of patients with insulinomas are diagnosed after a 24 hour fast and 90-94% at 48 hours.
Although some experts advocate conducting the prolonged fast for only 48 hours others disagree, arguing
that prolonging the fast up to 72 hours minimizes misdiagnosis and maximizes the probability of diagnosing
an insulinoma (30-31).
Limitations of the prolonged fast:
Normal subjects, especially young women, can occasionally have plasma glucose levels of <40
mg/dl (2.2 mmol/l)
Rare insulinomas suppress their release of insulin in response to hypoglycemia
Insulin levels can sometimes be artificially elevated in the presence of anti-insulin antibodies.
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Anti-Insulin Antibodies
Autoimmune hypoglycemia is a rare condition whereby antibodies, either directed against insulin or against
the insulin receptor, are responsible for hypoglycemia. Autoimmune hypoglycemia due to insulin-antibodies
should be suspected when the hypoglycemia is associated with high insulin levels (usually >100 uU/ml) and
incompletely suppressed C-peptide levels. Insulin levels are rarely >100 uU/ml in the presence of
hypoglycemia due to an insulinoma. Although these elevated insulin levels can be observed with exogenous
insulin administration, the associated c-peptide levels are usually extremely low. Autoimmune
hypoglycemia is most often seen in people of Japanese descent, but has been described in other populations
(37). Autoimmune hypoglycemia may also be due to antibodies to the insulin receptor. These patients will
have mildly elevated insulin levels (thought to be due to decreased clearance of insulin) and suppressed c-
peptide levels, and may have other autoimmune conditions (26). Insulin antibody testing does not need to be
done at the time of hypoglycemia.
Imaging
When endogenous hyperinsulininemic hypoglycemia is present, imaging studies are performed. These may
include computed tomography, magnetic resonance imaging (MRI), and/or transabdominal and endoscopic
ultrasonography. Imaging studies are successful in identifying approximately 75% of insulinomas (41).
Intraoperative pancreatic ultrasonography may also be used to localize small insulinomas not otherwise
found with other imaging modalities. Insulinomas are often less than 1.0 cm, so negative imaging does not
exclude the diagnosis (42-46).
TREATMENT
Immediate treatment should be focused on reversing the hypoglycemia. If the patient is able to ingest
carbohydrates 15 to 20 grams of glucose should be given every 15 minutes until the hypoglycemia has
resolved. If the patient is unable to ingest carbohydrates, or if the hypoglycemic episode is severe, parenteral
glucose should be administered. In a healthcare setting intravenous dextrose is used. Twenty-five gram
boluses of 50% dextrose are given until the hypoglycemia has resolved. If needed, an infusion of 10% or
20% dextrose can be used to sustain euglycemia in patients with recurrent episodes of hypoglycemia. In the
outpatient setting, glucagon, given as an intramuscular injection, is used to correct hypoglycemia. Glucose
gel and other forms of oral glucose should be used in impaired patients with caution and only in
circumstances where no alternative is available, as they pose an aspiration risk.
Long-term treatment should be tailored to the specific hypoglycemic disorder, taking into account the
burden of hypoglycemia on well-being and patient preferences. Offending medications should be
discontinued and underlying illnesses treated, whenever possible.
Surgical Treatment
Surgical resection can be curative for insulinomas. Most patients with successful surgical removal will have
good long term outcomes (54, 55). Surgery can also alleviate hypoglycemia in nonislet cell tumors, even if
the cancer cannot be cured. Radiotherapy and chemotherapy can also be used in nonislet cell tumors. Partial
pancreatectomy can be considered in patients with noninsulinoma pancreatogenous hypoglycemia. Results
of selective arterial calcium stimulation testing can be used to guide the area(s) of resection when partial
pancreatectomy is needed.
Dietary Treatment
In noninsulinoma pancreatogenous hypoglycemia, including patients with post Roux-en-Y gastric bypass
hypoglycemia, dietary interventions may be helpful. Frequent feedings and a low carbohydrate diet are
common recommendations (22-24, 56-57). Low carbohydrate diets are broadly defined in the literature, with
the macronutrient content from carbohydrates ranging from 2% to 30% (57-58). In post Roux-en-Y gastric
bypass hypoglycemia, restriction of carbohydrates, and avoidance of high glycemic index foods and simple
sugars are recommended. In severe cases gastrostomy tube feeding is sometimes needed.
Medical Treatment
Medical treatment with α-glucosidase inhibitors, calcium channel blockers, diazoxide,or octreotide can be
used if resection is not possible in patients with hyperinsulinism, or as a temporizing measure (Table 5).
Alpha glucosidase inhibitors (such as acarbose) delay the digestion of ingested carbohydrates, resulting in
lower blood glucose concentrations after meals. This medication may be useful in lessening the
hyperinsulinism in post Roux-en-Y gastric bypass hypoglycemia. It is typically prescribed as 50 mg three
times daily with meals (23, 57, 59).
Calcium channel blockers mediate hypoglycemia by inhibiting glucose stimulated insulin secretion from the
pancreatic beta-cells; verapamil 80 mg twice daily has been reported in the literature, but other agents such
as diltiazem and nifedipine have been used as well (23, 59).
Diazoxide inhibits insulin secretion by opening the ATP-dependent potassium channel of the beta cell in the
pancreas. Diazoxide is given orally as 3-8 mg/kg/day divided every 8-12 hours up to 1200 mg/day.
Diazoxide may cause edema, dizziness, nausea and hirsutism, and the dose should be reduced in the
presence of renal insufficiency (23, 60-61)
Somatostatin analogs (such as octreotide) inhibit insulin secretion when given in high doses, but may not be
as effective as diazoxide Octreotide is given as a subcutaneous injection 100 mcg twice daily up to 1500
mcg daily (23, 62).