Definition
Hypoglycemia is a clinical syndrome of diverse etiologies characterized by episodes of low blood glucose. These episodes are typically marked by autonomic manifestations such as trembling, sweating, nausea, and, in more severe episodes, central nervous system manifestations (neuroglycopenia) such as dizziness, confusion, and headache.
Classification
Hypoglycemic disorders have long been categorized as fasting or postprandial (reactive). This classification lacks practical value. Insulinoma, which is the archetypal cause of fasting hypo-glycemia, may produce symptoms postprandially and, indeed, in some cases solely postprandially. Patients with factitious hy-poglycemia evince symptoms irrespective of meals.
A more useful approach for the practitioner is a classification based on the patient’s clinical characteristics. Persons who appear otherwise healthy have hypoglycemic disorders different from those of persons who are ill.
Hypoglycemia in apparently healthy patients
In apparently healthy persons, single episodes of hypo-glycemia may result from accidental drug ingestion (e.g., ethanol in children). In addition to ethanol, salicylates and quinine can lower blood glucose levels; the combined effects of ethanol and quinine are responsible for so-called gin-and-tonic hypoglycemia. The healthy-appearing adult patient with a history of repeated episodes of neuroglycopenia usually has a disorder involving excessive insulin production, such as insulinoma; rarely, the hy-poglycemia is factitious, caused by surreptitious or inadvertent use of a hypoglycemic agent (e.g., insulin or a sulfonylurea) [see Conditions That Cause Hypoglycemia, below].
Hypoglycemia may occur in patients who have coexistent disease but whose disease is being controlled with medical treatment. Typically, the hypoglycemia in these cases is a side effect of the medication being used to treat the coexistent disease, or it results from the mistaken dispensing of a sulfonylurea instead of the prescribed drug.
Hypoglycemia in ill patients
Illness can lead to hypoglycemia through a variety of mechanisms, only some of which involve insulin and not all of which are known. Many illnesses (e.g., renal failure and sepsis) are known to pose the risk of low blood glucose levels [see Table 1]; hypoglycemia in a patient with one of these illnesses requires little if any investigation of its cause. However, not all patients with a disease that has a proclivity to generate hypoglycemia actually experience low blood glucose levels. Why only some ill patients experience hypoglycemia is unknown.
Hospitalized patients are at increased risk for hypoglycemia, often from iatrogenic factors. In any inpatient with hypoglycemia, medication should be considered a potential cause.
Low blood glucose levels may be found on laboratory testing of ill patients who have no symptoms of hypoglycemia. In patients with leukemia or severe hemolysis, the hypoglycemia may be an artifact resulting from consumption of glucose in the blood collection tube by large numbers of leukocytes or by nucleated red blood cells, respectively.1,2 Patients with glycogen storage disease may be asymptomatic because they have adapted to lifelong hypoglycemia from their disease.3
Diagnosis
Although the diagnosis of hypoglycemia requires the measurement of blood glucose, such measurement often is not feasible when symptoms arise during activities of ordinary life. Under these circumstances, the physician must take a detailed history to determine whether to proceed with further evaluation. The history should include a full description of the patient’s symptoms and the circumstances under which they occur.
A medication history is also an important aspect of the evaluation in a patient with clinical manifestations of hypoglycemia, especially if the onset coincides with the filling of a new prescription. Because of the potential for drug error, all medications taken by the patient should be identified by a medical professional, such as a physician or pharmacist.
Clinical manifestations
The symptoms of hypoglycemia have been classified into two major groups: autonomic and neuroglycopenic. In a study of experimentally induced hypoglycemia in diabetic and nondiabetic persons, a principal-components analysis assigned sweating, trembling, feelings of warmth, anxiety, and nausea to the auto-nomic group and dizziness, confusion, tiredness, difficulty in speaking, headache, and inability to concentrate to the neurogly-copenic group. Hunger, blurred vision, drowsiness, and weakness could not be confidently assigned to either group.4 In a retrospective analysis of 60 patients with insulinomas, 85% had various combinations of diplopia, blurred vision, sweating, palpitations, and weakness; 80% had confusion or abnormal behavior; 53% had amnesia or went into coma during the episode; and 12% had generalized seizures.5
The symptoms of hypoglycemia differ between persons but are nevertheless consistent from episode to episode in any one person.6,7 There is no consistent chronologic order to the evolution of symptoms; autonomic symptoms do not always precede neu-roglycopenic ones. In many patients, neuroglycopenic symptoms are the only ones observed.7 Patients who have autonomic symptoms only are unlikely to have a hypoglycemic disorder. An additional factor that influences the generation of symptoms in hy-poglycemia is their blunting by earlier hypoglycemic episodes.
Physical examination
In patients who appear healthy, with or without coexistent compensated disease, the physical examination is normal or reveals only minor abnormalities that are unlikely to be germane to the underlying hypoglycemic disorder. In patients suspected of having factitious hypoglycemia from injection of insulin, a search for needle-puncture sites is fruitless. In ill patients with a primary disorder that can cause hypoglycemia, the results of physical examination will reflect that disease. For the patient observed while hypoglycemic, findings may include diaphoresis,widened pulse pressure, and neurologic abnormalities ranging from slowed mentation or withdrawal from spontaneous communication to more overt confusion, erratic behavior, coma, seizure, and hypothermia.
Table 1 Causes of Hypoglycemia
|
Drugs |
Disopyramide |
|
Ethanol |
|
|
Haloperidol |
|
|
Quinine |
|
|
Salicylates |
|
|
Drugs in specific illnesses |
Pentamidine in Pneumocystis pneumonia |
|
Propoxyphene in renal failure |
|
|
Quinine in malaria |
|
|
Trimethoprim-sulfamethoxazole in renal failure |
|
|
Topical salicylates in renal failure |
|
|
Endogenous hyperinsulinism |
Insulinoma |
|
Islet hyperplasia/nesidioblastosis |
|
|
Persistent hyperinsulinemic hypoglycemia |
|
|
of infancy |
|
|
Noninsulinoma pancreatogenous |
|
|
hypoglycemia syndrome |
|
|
Insulin autoimmune hypoglycemia |
|
|
Neonatal |
|
|
Infant small for gestational age |
|
|
Erythroblastosis fetalis |
|
|
Infant of diabetic mother |
|
|
Cyanotic congenital heart disease |
|
|
Beckwith-Wiedemann syndrome |
|
|
Inherited |
|
|
Defects in amino acid and fatty acid |
|
|
metabolism |
|
|
Glycogen storage disease |
|
|
Hereditary fructose intolerance |
|
|
Isolated adrenocorticotropic hormone (ACTH) |
|
|
deficiency |
|
|
Isolated growth hormone deficiency |
|
|
Conditions that predispose to hypoglycemia |
Acquired |
|
Addison disease |
|
|
Carnitine deficiency |
|
|
Intense exercise |
|
|
Hypopituitarism |
|
|
Heart failure |
|
|
Lactic acidosis |
|
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Severe liver disease |
|
|
Postoperative status |
|
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Renal failure |
|
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Reye syndrome |
|
|
Sepsis |
|
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Shock |
|
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Spinal muscular atrophy |
|
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Starvation |
|
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Anorexia nervosa |
|
|
Large mesenchymal tumors (fibroma, sarcoma, |
|
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small cell carcinoma, mesothelioma) |
Laboratory tests
Serum Glucose
Studies of acute insulin-induced hypoglycemia in healthy persons have shown that the threshold for the development of symptoms is a serum glucose concentration of approximately 60 mg/dl; the threshold for impairment of brain function is approximately 50 mg/dl.8,9 These measurements were taken from arte-rialized venous blood (i.e., blood drawn from a vein in a heated hand [the application of heat shunts arterial blood into the venous system]); comparable levels in venous blood would probably be about 3 mg/dl lower. The rate of decrease in the serum glucose level does not influence the occurrence of the symptoms and signs of hypoglycemia.
Because symptoms of hypoglycemia are nonspecific, it is necessary to verify their origin. This is accomplished by applying a set of criteria first proposed by Whipple in 1938. The Whipple triad comprises spontaneous symptoms consistent with hypo-glycemia, a low serum glucose concentration at the time the symptoms occur, and relief of the symptoms through normalization of the glucose level.
A normal serum glucose concentration, reliably obtained during the occurrence of spontaneous symptoms, eliminates the possibility of a hypoglycemic disorder. Capillary glucose measurements that patients take themselves with a blood glucose meter during the occurrence of spontaneous symptoms are often unreliable, because nondiabetic patients usually are not experienced in this technique and because the measurements are obtained under adverse circumstances. Patients with a confirmed low serum glucose level (< 50 mg/dl) or a history of neurogly-copenic symptoms should undergo further testing. This is best accomplished with a prolonged fast.
The Prolonged (72-Hour) Fast
The prolonged (72-hour) fast is the classic diagnostic test for hypoglycemia. It should be conducted in a standardized manner [see Table 2]. The fast may be undertaken to demonstrate the Whipple triad and thereby establish that hypoglycemia is the basis for the patient’s symptoms. If the Whipple triad has already been documented, the fast may be conducted for the purpose of determining the mechanism of the hypoglycemia, through measurement of beta cell polypeptide and plasma sulfonylurea levels. In the latter case, the fast can be terminated when the serum glucose level drops to 55 mg/dl or less (or, better yet, < 50 mg/dl), which is the concentration at which beta cell polypep-tides should be suppressed. Not all patients will need the full 72 hours to accomplish the purpose for the fast. In a study of 170 patients with surgically proven insulinomas, termination of the fast occurred within 12 hours in 33% of patients, within 24 hours in 65%, within 36 hours in 84%, within 48 hours in 93%, and within 72 hours in 99%." Truncation of the fast at 48 hours, if hy-poglycemia has not occurred by then, risks misdiagnosis.
Starting the fast overnight has allowed 40% of patients (including those with insulinoma and other causes of hypo-glycemia) to conclude their fast in the outpatient endocrine-testing unit. Patients whose fast is not completed by the end of the business day are admitted to the hospital to complete the fast.
The decision whether to end the fast may not be easy to make when the Whipple triad is the goal. Because of delays in the availability of glucose measurements, the bedside glucose meter may have to serve as a guide. Some patients have slightly depressed glycemic levels without symptoms or signs of hypo-glycemia. In other patients, fasting evokes the symptoms they experience in ordinary life but their serum glucose levels are not in the hypoglycemic range. In such instances, symptoms cannot be attributed to hypoglycemia. To complicate matters, young, lean, healthy women—and, to a lesser degree, some men—may have serum glucose concentrations in the range of 40 mg/dl or even lower during prolonged fasting.12 Careful examination and testing for subtle signs or symptoms of hypoglycemia should therefore be conducted repeatedly when the patient’s serum glucose level is near or in the hypoglycemic range. To end the fast solely on the basis of a low serum glucose level, in the absence of symptoms or signs of hypoglycemia, may jeopardize accurate diagnosis. On the other hand, failing to appreciate the manifestations of neuroglycopenia and, hence, concluding that the results of the fast are negative is an equally egregious error. It is essential to monitor patients closely during the fast and to be vigilant for subtle signs of neuroglycopenia.
Beta Cell Polypeptides and Their Surrogates
Concentrations of beta cell polypeptides (insulin, C-peptide, and proinsulin) are interpreted in the context of the concomitant serum glucose concentration. The normal overnight fasting ranges for these polypeptides do not apply when the serum glucose level is low. When immunochemiluminometric assays (ICMA) are used, the criteria for endogenous hyperinsulinemia are as follows: serum insulin, 3 ^U/ml or greater; C-peptide, 200 pmol/L or greater; and proinsulin, 5 pmol/L or greater [see Figure 1].13
Insulin concentrations rarely exceed 100 ^U/ml in patients with insulinomas. Values above this level suggest recent insulin administration or the presence of insulin antibodies.
Ratios of glucose to insulin, and vice versa, have no diagnostic utility [see Figure 1 ]. The molar ratio of insulin to C-peptide is the same for patients with insulinomas and healthy persons (approximately 0.2). The molar ratio of proinsulin to insulin appears to be higher in persons with insulinoma, but it provides poor diagnostic utility.
Because insulin has an antiketogenic effect, serum levels of the ketone body |-hydroxybutyrate can be used as a surrogate for measurement of insulin. The serum |-hydroxybutyrate level is low—2.7 mmol/L or less—in patients with insulin-mediated hypoglycemia; normal persons and those with non-insulin-mediated hypoglycemia have higher levels [see Figure 1].13
At the end of the fast, the patient is given an intravenous dose of 1 mg of glucagon, and the subsequent glucose response is measured. Because insulin is glycogenic and antiglycogenolytic, the glucagon injection results in an increase in the serum glucose level of 25 mg/dl or greater in patients with insulin-mediated hypoglycemia, whereas normal persons or those with non-in-sulin-mediated hypoglycemia have lesser increases [see Figure 1].13 An exuberant serum insulin response to intravenous glucagon has been considered an indication of insulinomas, but unfortunately, no normative data have been generated for this test. Measurement of beta cell polypeptides and insulin surrogates (| -hydroxybutyrate and glucose response to intravenous glucagon) has diagnostic utility only when the serum glucose level is 60 mg/dl or lower at the end of the fast.
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Table 2 Protocol for Prolonged Supervised Fast |
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1. Date the onset of the fast as of the last ingestion of calories. Discontinue all nonessential medications. |
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2. Allow the patient to drink calorie-free and caffeine-free beverages. |
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3. Ensure that the patient is active during waking hours. |
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4. Measure plasma glucose, insulin, C-peptide, and, if an assay is available, proinsulin in the same specimen. Repeat measurements every 6 hr until the plasma glucose drops below 60 mg/dl; then repeat the measurements every 1-2 hr. |
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5. When the plasma glucose is less than 45 mg/dl and the patient has symptoms or signs of hypoglycemia, measure plasma glucose, insulin, C-peptide, proinsulin, |-hydroxybutyrate, and sulfonylurea in the same specimen; then inject 1 mg of glucagon I.V. and measure plasma glucose after 10, 20, and 30 min. |
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6. Feed the patient. |
Sulfonylureas and Meglitinides
Persons with hypoglycemia from inappropriate use of sul-fonylureas or meglitinides (e.g., repaglinide) have concentrations of beta cell polypeptides that are identical to those observed in persons with insulinoma. Consequently, plasma assays for these drugs is an essential aspect of the evaluation. I use a highly sensitive and accurate liquid chromatographic tandem mass spectroscopy method to identify these drugs. A positive assay suggests either covert or inadvertent usage.
Insulin Antibodies
An assay for insulin antibodies should be done in every patient with clear evidence of hypoglycemia. The detection of insulin antibodies in a nondiabetic patient was once considered to be firm evidence of insulin factitious hypoglycemia, especially when animal insulin was the only commercially available type. Currently, most patients with factitious hypoglycemia have no detectable insulin antibodies, possibly because of the use of human insulin, which is less antigenic than beef or pork insulin. Rather, the presence of insulin antibodies, especially in high titers, is diagnostic of insulin autoimmune hypoglycemia (IAH) (see below).13 Very low titers of insulin antibodies may sometimes be detected in persons without hypoglycemia14 and, in rare instances, in patients with insulinomas.
