INTRODUCTION — Hypoglycemia is an uncommon clinical problem in patients not being treated for diabetes mellitus. It can occur in the fasting or postprandial state. In any case of hypoglycemia, regardless of the cause, the diagnosis can usually be established by appropriate blood tests at the time of the spontaneous occurrence of hypoglycemia, if such an event occurs in the presence of medical personnel (table 1).
If the patient is not symptomatic when seen, the diagnostic strategy is to replicate conditions in which hypoglycemia would be expected if a hypoglycemic disorder exists. A prolonged supervised fast, which can last as long as 72 hours, has been the best established and probably most reliable test for the evaluation of hypoglycemia occurring in the food-deprived state. For patients with postprandial hypoglycemia, however, a mixed-meal test is the preferred provocative procedure.
This topic will review the approach to the nondiabetic patient with hypoglycemia. The clinical manifestations, diagnosis, and causes of hypoglycemia, in general, are discussed separately (table 2 and table 3). The evaluation and management of hypoglycemia in patients with drug-treated diabetes mellitus is also reviewed separately. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis, and causes" and "Diagnostic dilemmas in hypoglycemia: Illustrative cases" and "Hypoglycemia in adults with diabetes mellitus".)
CANDIDATES FOR EVALUATION — The presence of a hypoglycemic disorder in a person without diabetes should not be suspected solely on the basis of a low plasma glucose concentration [1], as this observation is necessary but insufficient for a diagnosis and, in some cases, may be misleading. Only those patients in whom Whipple's triad is documented require evaluation and management of hypoglycemia.
Whipple's triad includes the following:
●Symptoms consistent with hypoglycemia
●A low plasma glucose concentration measured with a precise method (not a home glucose monitor) when symptoms are present
●Relief of those symptoms after the plasma glucose level is raised
Given documentation of Whipple's triad, detailed laboratory evaluation is usually required in a healthy-appearing patient, whereas hypoglycemia may be readily recognized as part of the underlying illness or its treatment (or prescribing/dispensing error) in an ill or medicated patient (table 2). (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis, and causes", section on 'Clinical manifestations'.)
It is important to confirm the presence of a hypoglycemic disorder before performing various tests to determine the etiology of hypoglycemia. The association of symptoms reinforces the biologic significance of the low blood glucose. Healthy individuals may have low glucose concentrations without symptoms after prolonged fasting. In addition, sympathoadrenal and neuroglycopenic symptoms may be highly suggestive of hypoglycemia, but they cannot be ascribed to hypoglycemia with confidence unless the glucose concentration is low at the same time. Normal glucose concentrations measured when the patient is free of those symptoms does not exclude the possibility of hypoglycemia at the time of those earlier symptoms. Documentation of Whipple's triad helps to establish the existence of a hypoglycemic disorder [2].
Hypoglycemia is sometimes detected serendipitously. A low plasma glucose concentration in the absence of symptoms of hypoglycemia suggests the possibility of artifactual hypoglycemia. However, a distinctly low plasma glucose concentration measured in a reliable laboratory cannot be ignored. The measurement should be repeated using a collection tube that contains an inhibitor of glycolysis, and processing should not be delayed. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis, and causes", section on 'Differential diagnosis'.)
Although low blood glucose values measured using reflectance meters suggest the presence of hypoglycemia, these methods are not reliable to diagnose hypoglycemia in the absence of diabetes treated with a medication such as insulin or a sulfonylurea that can cause hypoglycemia. Thus, a patient who has a single low blood glucose value measured by a meter but no symptoms of hypoglycemia probably does not need further evaluation; on the other hand, evaluation is indicated in a patient who has repeated low values.
Patients who have only sympathoadrenal symptoms but normal concurrent plasma glucose concentrations have a low probability of having a hypoglycemic disorder and do not require a comprehensive evaluation for a hypoglycemic disorder. This combination is most common in patients with postprandial symptoms. (See "Evaluation of postprandial symptoms of hypoglycemia in adults without diabetes".)
APPROACH TO TESTING — Our approach to the evaluation and management of hypoglycemia in nondiabetic adults is outlined below. Because hypoglycemic disorders are uncommon in persons without diabetes, this approach is largely based upon clinical experience [1]. This approach was endorsed by the 2009 Endocrine Society guidelines for the evaluation and management of hypoglycemic disorders in adults [2].
Clinical evaluation — The first step is to review the patient's history in detail, including the nature and timing of symptoms (particularly in relationship to meals), existence of underlying illnesses or conditions, medications taken by the individual and by family members, and social history. Clinical evidence for adrenal insufficiency or nonislet cell tumor should be considered. In a patient with documented hypoglycemia, the cause may be apparent from the history and physical examination (table 2). In a seemingly well individual, the cause is less apparent and may be due to hyperinsulinism or factitious hypoglycemia. When the cause of hypoglycemia is not evident, detailed laboratory evaluation is needed.
Laboratory testing — The presence of a hypoglycemic disorder in a person without diabetes should not be inferred solely on the basis of a low plasma glucose concentration, unless the value is severely depressed (<40 mg/dL [2.2 mmol/L]). To rule out artifactual hypoglycemia in such cases, the measurement should be repeated using a collection tube that contains an inhibitor of glycolysis, and processing should not be delayed. (Related Lab Interpretation Monograph(s): "Low glucose in adults".)
The purpose of the initial laboratory evaluation is to document Whipple's triad [1]. Should Whipple's triad have been demonstrated previously, the goal of testing is to assess the role of insulin in the genesis of the hypoglycemia.
If the patient is not symptomatic when seen, the diagnostic strategy is to seek Whipple's triad under conditions in which hypoglycemia would be expected if a hypoglycemic disorder exists. In a patient who presents with a self-diagnosis of hypoglycemia, one strategy is to measure plasma glucose concentrations at the time of symptoms, and then decide if the glucose values and the history are sufficiently suggestive to warrant additional evaluation. This strategy is reasonable if the patient has infrequent symptoms and the suspicion is not high enough to embark immediately on provocative testing.
If the symptoms occur primarily in the fasting state, the initial evaluation should be performed during a fast (see 'Fasting evaluation' below). However, if there is a compelling history of postprandial symptoms, it is reasonable to seek Whipple's triad with frequent, timed plasma glucose measurements and recording of any symptoms after a mixed meal. (See 'Postprandial evaluation' below.)
Patients who are fortuitously observed during an episode of symptoms and are found to have hypoglycemia at that time should have the following blood tests (table 1) (related Lab Interpretation Monograph(s): "Low glucose in adults"):
●Glucose
●Insulin
●C-peptide
●Beta-hydroxybutyrate (BHOB)
●Proinsulin
●Sulfonylurea and meglitinide screen
The interpretation of these results is shown in the table (table 4) and described below. (See 'Interpretation of data' below and 'Determining the cause of hypoglycemia' below.)
In patients with endogenous hyperinsulinism, insulin antibodies should be measured to distinguish insulin autoimmune hypoglycemia from other causes of hyperinsulinism (table 2 and table 4). Insulin antibodies do not need to be drawn during hypoglycemia.
Fasting evaluation — There are patients in whom symptoms occur after only a short period of food withdrawal. In such patients, continued observation in the office or clinic, especially if they have fasted overnight, may result in an episode of symptomatic hypoglycemia [1]. Plasma glucose should be measured repeatedly during the period of observation. If symptoms occur and hypoglycemia is documented (plasma glucose <55 mg/dL [3 mmol/L]), the other tests described above should be performed (table 4). The results may obviate the need for a provocative test, such as the 72-hour fast.
If this approach causes neither symptoms nor hypoglycemia and if clinical suspicion remains high, the patient should undergo a 72-hour fast. (See '72-hour fast' below.)
Postprandial evaluation — If symptoms of hypoglycemia typically occur within five hours after eating, patients should be evaluated in the postprandial state (mixed-meal test).
For a mixed-meal diagnostic test, the patient consumes a non-liquid meal that usually leads to symptoms and is then observed for up to five hours [1]. Samples are collected for plasma glucose, insulin, C-peptide, and proinsulin prior to ingestion of the meal and every 30 minutes thereafter for five hours. If severe symptoms occur prior to five hours, samples for the above lab tests should be collected before the administration of carbohydrates (to assess for correction of symptoms). All glucose samples are sent for analysis. The samples for insulin, C-peptide, and proinsulin should be analyzed only in those samples in which plasma glucose is <60 mg/dL (3.3 mmol/L). If Whipple's triad is demonstrated, sulfonylureas, meglitinides, and antibodies to insulin should also be measured.
Standards for the interpretation of the mixed-meal test are not established. Thus, the interpretation of these test results is similar to when tests are done during a spontaneous episode of hypoglycemia or during a 72-hour fast (table 4). However, proinsulin has a much longer half-life in the circulation than insulin and accumulates for >2 hours after a meal [3,4]. (See 'Interpretation of data' below.)
An oral glucose tolerance test (OGTT) or a meal that is solely in liquid form (eg, Ensure) done in an effort to replicate postprandial symptoms should not be performed, because misleading results may be obtained, particularly in patients with prior upper gastrointestinal surgery and disordered gastric emptying in whom a liquid meal may precipitate dumping syndrome [5]. (See "Evaluation of postprandial symptoms of hypoglycemia in adults without diabetes", section on 'Postprandial syndrome'.)
72-hour fast — The purpose of the 72-hour fast is to provoke the homeostatic responses that keep blood glucose concentrations from falling to concentrations that cause symptoms in the absence of food. Increased release of glucagon, epinephrine, and, to a lesser degree, growth hormone and cortisol are the most important components of this response. All the hormonal responses begin well before the onset of symptomatic hypoglycemia. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)
Normal individuals do not have symptomatic hypoglycemia after a prolonged fast, because of a hormonally mediated increase in glucose production and/or lipolysis and ketone body production. Gluconeogenesis accounts for approximately 50 percent of glucose production after an overnight fast and for almost all glucose production after 42 hours or more of fasting [6].
The prolonged fast will result in hypoglycemia only if there is a defect in the ability to maintain normoglycemia due, for example, to an excess of insulin, which inhibits endogenous glucose production, as well as the transition to alternate sources of fuel and subsequent ketone production. The defect should be identifiable if appropriate testing is performed (table 4). (See 'Interpretation of data' below.)
Protocol — The 72-hour fast can be initiated at home, usually after the evening meal, and continued the next day in an outpatient setting or a hospital.
The following protocol is used at our institution (Mayo Clinic, Rochester, MN) [7], whether the fast is initiated in the outpatient setting or in the hospital. A careful record should be kept of exactly what was done, what blood samples were taken, what was to be measured in each blood sample, and what symptoms occurred. It is equally important that the blood samples and laboratory slips be carefully labeled, particularly with the exact time, and that the labeling information be recorded on a flow sheet. Later interpretation of the results is possible only with this detail.
●Date the onset of the fast at the time of the last intake of calories. Discontinue all nonessential medications.
●Allow the patient to drink beverages that are calorie and caffeine free.
●Ensure that the patient is active during waking hours.
●Collect blood specimens for measurement of plasma glucose, insulin, C-peptide, proinsulin, and BHOB every six hours until the glucose concentration is below 60 mg/dL (3.3 mmol/L); at this point, the frequency of sampling should be increased to every one to two hours. Because of possible delays in the availability of the results of plasma glucose testing, a bedside reflectance meter may have to be used to measure blood glucose when frequent samples are obtained. However, the decision to end the fast should not be made on the basis of a fingerstick blood glucose value. It is essential that the clinician determine in advance the correct tubes to use for the blood samples and the correct procedures for handling and processing the samples.
Although blood is collected repeatedly, we measure insulin, C-peptide, and proinsulin only in those specimens in which the plasma glucose concentration is ≤60 mg/dL (3.3 mmol/L).
Insulin antibodies should be measured, but they do not have to be measured during hypoglycemia.
Test endpoints and duration — The fast is ended when the plasma glucose concentration is ≤45 mg/dL (2.5 mmol/L), the patient has symptoms or signs of hypoglycemia, 72 hours have elapsed, or when the plasma glucose concentration is less than 55 mg/dL (3 mmol/L) if Whipple's triad was documented on a prior occasion [1,2].
Fasting for a maximum of 72 hours has been the standard test for the diagnosis of insulinoma. A 48-hour maximum has been proposed as a simpler alternative based upon a report of 127 patients with insulinoma in which adequate information was obtained for diagnosis in all patients [8]. The fast was terminated because of hypoglycemia (plasma glucose ≤45 mg/dL [2.5 mmol/L]) in 43 percent by 12 hours, 67 percent by 24 hours, and 95 percent by 48 hours.
However, in our series of 205 patients with insulinoma, 14 percent did not develop Whipple's triad until after 48 hours of fasting [9]. Thus, to avoid misdiagnosis, we recommend the standard 72-hour fast.
The decision to end the fast may not be easy. Some patients have slightly low plasma glucose values but no symptoms or signs of hypoglycemia, while others have the same symptoms during fasting that they have in ordinary life at a time when plasma glucose values are normal. In the latter patients, the symptoms cannot be attributed to hypoglycemia. To complicate matters further, young, lean, healthy women may have plasma glucose concentrations in the range of 40 mg/dL (2.2 mmol/L) or even lower after prolonged periods of fasting [10].
Careful questioning and testing for subtle symptoms or signs of hypoglycemia should be conducted repeatedly when the patient's plasma glucose is near or in the hypoglycemic range. Simple tests of cognitive function may be indicated. To end the fast solely on the basis of a low plasma glucose value (except in those patients who have had Whipple's triad documented previously), in the absence of symptoms or signs of hypoglycemia, jeopardizes the possibility of discriminating between normal persons and those with hypoglycemia not mediated by insulin. A low plasma glucose value is a necessary, but not sufficient, finding for the diagnosis of hypoglycemia.
The absence of symptoms or signs of hypoglycemia and lack of a low plasma glucose concentration during a 72-hour fast indicates a normal 72-hour fast but does not preclude the existence of a hypoglycemic disorder that causes only postprandial symptoms.
Ending the fast — Three steps are performed at the end of the fast:
●Collect samples for plasma glucose, insulin, C-peptide, proinsulin, BHOB, and oral hypoglycemic agents
●1 mg of glucagon is given intravenously and the plasma glucose measured 10, 20, and 30 minutes later
●The patient is fed
Interpretation of data — Interpretation of the data obtained at the end of the 72-hour fast is the same as that performed during the occurrence of a spontaneous hypoglycemic episode (table 4) [7,11]. These data will help distinguish hyperinsulinemia (endogenous or exogenous) from other causes of hypoglycemia. The normal overnight fasting reference ranges usually supplied by the laboratory for plasma insulin, C-peptide, proinsulin, and BHOB, as well as the response of plasma glucose to intravenous glucagon, cannot be applied when the plasma glucose is in the hypoglycemic range. New criteria are required.
In addition, ratios of insulin-to-glucose or of glucose-to-insulin are not helpful in the establishment of hyperinsulinemia; absolute values for insulin are preferable [12].
The distribution of simultaneously measured plasma glucose and insulin concentrations in patients with surgically confirmed insulinomas and in normal subjects studied during 72-hour fasts is shown in the figure (figure 1) [7]. The recommended diagnostic criteria for plasma insulin, C-peptide, proinsulin, and BHOB, described below, have sensitivities and specificities of >90 and >70 percent, respectively, for the diagnosis of insulinoma [13].
Plasma insulin — A plasma insulin concentration of 3 microU/mL (20.8 pmol/L) by immunochemiluminometric assay (ICMA) when the plasma glucose concentration is below 55 mg/dL (3.0 mmol/L) indicates an excess of insulin and is consistent with hyperinsulinemia (eg, insulinoma) (figure 1). Unfortunately, plasma glucose concentrations fall below 50 mg/dL (2.8 mmol/L) in some normal subjects and remain above 50 mg/dL in an occasional patient with an insulinoma. This slight overlap can occur despite best efforts to require a plasma glucose of less than 45 mg/dL (2.5 mmol/L) at the end of the fast because of the variation in plasma glucose in the hypoglycemic range.
Plasma insulin by ICMA may be lowered in a hemolyzed blood sample. Some insulin assays detect only human insulin, whereas others detect both human insulin and synthetic insulin analogs. It is important that the clinician knows which insulin assay is used and whether it measures human insulin, insulin analogs, or both. (See "Factitious hypoglycemia", section on 'Insulin measurements'.)
Plasma C-peptide — It is essential to measure plasma C-peptide at the end of the fast; measurement of plasma proinsulin can also be helpful (figure 2) [14-16]. Plasma C-peptide distinguishes endogenous from exogenous hyperinsulinemia. In patients in whom plasma glucose concentrations fell below 45 mg/dL (2.5 mmol/L), there was no overlap in the values in insulinoma patients and normal subjects at a plasma C-peptide concentration of 0.2 nmol/L (200 pmol/L or 0.6 ng/mL). All insulinoma patients had higher values, and all normal subjects who were hypoglycemic had lower values. For plasma proinsulin, the diagnostic criterion for insulinoma is 5 pmol/L or greater (figure 3).
Plasma beta-hydroxybutyrate — Because of the antiketogenic effect of insulin, plasma BHOB concentrations are lower in insulinoma patients than in normal subjects. All patients with insulinoma had plasma BHOB values of 2.7 mmol/L or less at the end of the fast, whereas normal subjects had higher values (figure 4). A progressive rise in the concentration of BHOB after the 18-hour point of the fast is indicative of a negative fast [17].
The plasma BHOB value, as well as the glucose response to glucagon, can be used to confirm the diagnosis in patients in whom the insulin and C-peptide values are in the borderline range (eg, plasma insulin concentration of <3 microU/mL [20.8 pmol/L], C-peptide <0.2 nmol/L [0.6 ng/mL]) or to indicate the action of an insulin-like factor.
Glycemic response to glucagon — Insulin inhibits glycogenolysis and hyperinsulinemia permits retention of glycogen within the liver. As a result, patients with insulin-mediated hypoglycemia respond to 1 mg of intravenous glucagon (a potent glycogenolytic agent) by releasing glucose. Normal individuals will have released virtually all glucose from the liver at the end of the 72-hour fast and cannot therefore respond as vigorously to intravenous glucagon as a patient with an insulinoma. At the end of the fast, patients with an insulinoma have an increase in plasma glucose of 25 mg/dL (1.4 mmol/L) or more in 20 to 30 minutes, whereas normal individuals have a smaller increment (figure 5).
Determining the cause of hypoglycemia — By observing the presence of symptoms and signs of hypoglycemia and by making the above biochemical measurements, it is usually possible to distinguish among the various causes of hypoglycemia (table 2) [7].
A lower plasma BHOB value and a vigorous plasma glucose response to intravenous glucagon point to hypoglycemia mediated by insulin or an insulin-like factor (table 4).
●Plasma insulin, C-peptide, and proinsulin values are elevated in patients with insulinoma, oral hypoglycemia agent-induced hypoglycemia, and insulin autoimmune hypoglycemia.
Sulfonylurea or meglitinides are present in the plasma only in oral hypoglycemic agent-induced hypoglycemia [18]. (See "Factitious hypoglycemia".)
The presence of insulin or insulin receptor antibodies can distinguish insulin autoimmune hypoglycemia from insulinoma [19]. Insulin autoimmune hypoglycemia occurs in patients who have antibodies directed to endogenous insulin or to the insulin receptor. Symptoms can occur postprandially, fasting, or in both states. In patients with insulin autoantibodies, it is presumed that insulin secreted in response to a meal binds to the antibody and then disassociates in an unregulated fashion causing hyperinsulinemia and hypoglycemia. In patients with antibodies to the insulin receptor, hypoglycemia occurs as a result of antibody activation of the receptor.
●Plasma insulin, C-peptide, and proinsulin values are also elevated in patients with noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS). NIPHS is endogenous hyperinsulinemia due to islet hypertrophy and nesidioblastosis, a form of primary islet cell hypertrophy with neodifferentiation of islet of Langerhans cells from pancreatic duct epithelium. An unusual feature of this disorder is that hypoglycemia occurs postprandially, two to four hours after a meal. Fasting hypoglycemia, characteristic of insulinoma, is rare in this disorder. Nesidioblastosis has also been described in patients with post-gastric bypass hypoglycemia. (See "Noninsulinoma pancreatogenous hypoglycemia syndrome".)
●Plasma insulin values are high in patients with exogenous insulin administration, whereas plasma C-peptide and proinsulin values are low. In hypoglycemia caused by synthetic insulin analogs (eg, glargine, detemir, lispro, aspart), insulin concentrations may be low, depending upon the insulin assay used. Clinical suspicion should guide subsequent testing of the sample obtained at the time of hypoglycemia against a panel of antibodies to insulin capable of detecting various analogs. (See "Factitious hypoglycemia", section on 'Diagnosis'.)
●Plasma insulin, C-peptide, and proinsulin concentrations are not elevated in patients with nonislet cell tumors. Nonislet cell tumors can cause hypoglycemia via a number of mechanisms not related to hypersecretion of insulin, including tumor production of insulin-like growth factor-2 or more often its precursor, and tumor burden in which the tumor cell's high metabolic needs and reduced hepatic glycogen stores are thought to be responsible for hypoglycemia. (See "Nonislet cell tumor hypoglycemia" and "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Paraneoplastic syndromes'.)
LOCALIZING STUDIES — Localizing studies should not be performed until endogenous insulin-mediated hypoglycemia has been demonstrated. In patients with endogenous insulin-mediated hypoglycemia, the differential diagnosis includes insulinoma, nesidioblastosis/islet-cell hypertrophy, oral hypoglycemic agent-induced hypoglycemia, and insulin autoimmune hypoglycemia (table 2). Negative results for circulating oral hypoglycemic agents and insulin antibodies effectively rule out oral hypoglycemic agent-induced hypoglycemia and insulin autoimmune hypoglycemia, respectively. A localizing study is required in all patients with insulin-mediated hypoglycemia, except those with positive results for insulin antibodies or circulating oral hypoglycemic agents.
Radiologic studies — Computed tomography (CT), magnetic resonance imaging (MRI), and transabdominal ultrasonography can detect most insulinomas [20,21]. The choice of procedure depends upon which tests are available and local radiologic skill. Transabdominal ultrasonography is our preferred initial test. (See "Insulinoma", section on 'Tumor localization'.)
A negative imaging study does not exclude insulinoma. If an insulinoma is not visible with initial imaging, additional studies, such as endoscopic ultrasonography (sometimes with fine-needle aspiration biopsy of detected tumors) or selective arterial calcium stimulation, are required.
Selective arterial calcium stimulation — A selective arterial calcium stimulation test with hepatic venous sampling can be performed to distinguish between a focal abnormality (insulinoma) and a diffuse process (islet-cell hypertrophy/nesidioblastosis). We reserve this test for complex cases of endogenous hyperinsulinemic hypoglycemia and negative radiologic localization studies.
This test involves selective injection of calcium gluconate into the gastroduodenal, splenic, and superior mesenteric arteries with subsequent sampling of the hepatic venous effluent for insulin. A positive result is at least a doubling or tripling of basal insulin concentrations [22]. The increase in insulin occurs in samples from the artery supplying the region with hyperfunctioning islets, either an insulinoma or islet hypertrophy, which facilitates operative localization [23]. Understanding the local variation in pancreatic arterial anatomy is important for appropriate regionalization.
In patients with insulinoma, the response is positive in one artery alone unless the tumor resides in a "watershed" area fed by two arteries or the patient has multiple insulinomas scattered throughout the pancreas (table 5). A few patients have aberrant arterial anatomy that may explain multiple areas of response [23]. This arterial variant should be identifiable by the interventional radiologist performing the procedure. In patients with islet-cell hypertrophy, positive responses are usually but not always observed after injection of multiple arteries. (See "Insulinoma", section on 'Selective arterial calcium stimulation' and "Noninsulinoma pancreatogenous hypoglycemia syndrome", section on 'Localization studies' and "Diagnostic dilemmas in hypoglycemia: Illustrative cases".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Low blood sugar in people without diabetes (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Who should be evaluated?
•Only those patients in whom Whipple's triad is documented require evaluation and management of hypoglycemia. (See 'Candidates for evaluation' above.)
•In patients with symptoms of hypoglycemia, but normal plasma glucose concentrations at the same time, no further evaluation is needed.
•Although low blood glucose values measured using reflectance meters suggest the presence of hypoglycemia, these methods are not sufficiently reliable in the low range.
●Evaluation
•The first step is to review the patient's history in detail, including the nature and timing of symptoms (particularly in relationship to meals), existence of underlying illnesses or conditions, medications taken by the individual and by family members, and social history. In a patient with documented hypoglycemia, the cause may be apparent from the history and physical examination (table 2). When the cause of hypoglycemia is not evident, laboratory evaluation is needed. (See 'Clinical evaluation' above.)
•In patients who are fortuitously observed during an episode of symptoms and are found to have simultaneous hypoglycemia (fasting or postprandial), additional measurements should be performed (plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate [BHOB], and an oral hypoglycemic agent screen) (table 1). Studies at this time may obviate the need for further testing (table 4). (See 'Laboratory testing' above.) (Related Lab Interpretation Monograph(s): "Low glucose in adults".)
•If the patient is not symptomatic when seen, the diagnostic strategy is to seek Whipple's triad under conditions in which hypoglycemia would be expected if a hypoglycemic disorder exists (either fasting or during a mixed-meal test). (See 'Fasting evaluation' above and 'Postprandial evaluation' above.)
•If neither symptoms nor hypoglycemia have been observed and if clinical suspicion remains high, the patient should undergo a 72-hour fast, which is described in detail above. (See '72-hour fast' above.)
•An oral glucose tolerance test (OGTT) done in an effort to replicate postprandial symptoms should not be performed, because misleading results may be obtained. (See "Evaluation of postprandial symptoms of hypoglycemia in adults without diabetes".)
●Interpretation of test results
•Interpretation of the data obtained at the end of the 72-hour fast or a mixed-meal test is the same as that performed during the occurrence of a spontaneous hypoglycemic episode (table 4).
•A lower plasma BHOB value and a vigorous plasma glucose response to intravenous glucagon point to hypoglycemia mediated by insulin or an insulin-like factor (table 4). (See 'Interpretation of data' above.)
•Plasma insulin, C-peptide, and proinsulin values are elevated in patients with insulinomas, oral hypoglycemic agent-induced hypoglycemia, and insulin autoimmune hypoglycemia. Sulfonylurea or meglitinides are present in the plasma only in oral hypoglycemia agent-induced hypoglycemia. The presence of insulin or insulin receptor antibodies can distinguish insulin autoimmune hypoglycemia from insulinoma. (See 'Determining the cause of hypoglycemia' above and "Factitious hypoglycemia".)
•In patients with exogenous insulin administration, plasma insulin values are higher than levels observed in insulinoma, but plasma C-peptide and proinsulin values are low or undetectable. (See 'Determining the cause of hypoglycemia' above.)
•Hypoglycemia that is not mediated by insulin or an insulin-like factor is characterized by low plasma concentrations of insulin, C-peptide, and proinsulin. (See 'Determining the cause of hypoglycemia' above.)
Illustrative cases of hypoglycemia are found elsewhere. (See "Diagnostic dilemmas in hypoglycemia: Illustrative cases".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges F John Service, MD, PhD, now deceased, who contributed to an earlier version of this topic.
