ACP medicine, 3rd Edition

Endocrinology

Hypoglycemia

  1. John Service MD, PHD1

1Earl and Annette R. McDonough Professor of Medicine, Mayo Medical School

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

May 2007

Definition

Hypoglycemia is a clinical syndrome that has diverse causes and is characterized by episodes of low blood glucose. These episodes are typically marked by central nervous system manifestations (i.e., neuroglycopenia). Autonomic manifestations alone do not indicate a hypoglycemic disorder.

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 hypoglycemia, may produce symptoms postprandially and, indeed, in some cases solely postprandially. Patients with factitious hypoglycemia 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.

Etiology

Hypoglycemia in Apparently Healthy Patients

In apparently healthy persons, single episodes of hypoglycemia may result from accidental drug ingestion (e.g., ethanol in children). In addition to ethanol, salicylates and quinine can lower blood glucose levels. The healthy-appearing adult patient with a history of repeated episodes of neuroglycopenia usually has a disorder involving excessive insulin production, such as insulinoma or noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS); rarely, the hypoglycemia 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. Some illnesses (e.g., glycogen storage disease) have hypoglycemia as a clinical feature. Other illnesses, such as advanced liver disease, 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.

Table 1 Clinical Classification of Hypoglycemic Disorders

Patient appears healthy

No coexistent disease
  Drugs
    Ethanol
    Salicylates
    Quinine
    Haloperidol
  Insulinoma
  Islet hypertrophy/nesidioblastosis
    Persistent hyperinsulinemic hypoglycemia of infancy
    Noninsulinoma pancreatogenous hypoglycemia syndrome
    Postgastric bypass hypoglycemia
  Factitial hypoglycemia from insulin or sulfonylurea
  Severe exercise
  Ketotic hypoglycemia
Compensated coexistent disease
  Drugs
    Dispensing error
    Disopyramide
    Beta-adrenergic blocking agent
    Sulfhydryl or thiol-containing drugs with autoimmune insulin
    Unripe akee fruit and undernutrition

Patient appears ill

Drugs
  Pentamidine and Pneumocystis pneumonia
  Sulfamethoxazole/trimethoprim and renal failure
  Propoxyphene and renal failure
  Quinine and cerebral malaria
  Quinine and malaria
  Topical salicylates and renal failure
Predisposing illness
  Small for gestational age infant
  Beckwith-Wiedemann syndrome
  Erythroblastosis fetalis
  Infant of diabetic mother
  Glycogen storage disease
  Defects in amino acid and fatty acid metabolism
  Reye syndrome
  Cyanotic congenital heart disease
  Hypopituitarism
  Isolated growth hormone deficiency
  Isolated adrenocorticotropic hormone deficiency
  Addison disease
  Hereditary fructose intolerance
  Carnitine deficiency
  Defective type 1 glucose transporter in the brain
  Acquired severe liver disease
  Large non-beta cell tumor
  Sepsis
  Renal failure
  Congestive heart failure
  Lactic acidosis
  Starvation
  Anorexia nervosa
  Postoperative removal of pheochromocytoma
  Insulin receptor antibody hypoglycemia

Hospitalized patient

Diseases predisposing to hypoglycemia
Total parenteral nutrition and insulin therapy
Questran interference with glucocorticoid absorption
Shock

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 is best achieved by the measurement of blood glucose during the occurrence of spontaneous symptoms, such measurement often is not feasible. The physician must take a detailed history to determine the extent of the 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, the identity of all medications taken by the patient should be confirmed 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 autonomic group and dizziness, confusion, tiredness, difficulty in speaking, headache, and inability to concentrate to the neuroglycopenic 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 among 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 neuroglycopenic 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 hypoglycemia 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.

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 arterialized 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. Whipple's triad comprises spontaneous symptoms consistent with hypoglycemia, a low serum glucose concentration at the time the symptoms occur, and relief of the symptoms through normalization of the glucose level.10

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 neuroglycopenic symptoms should undergo further testing. This is best accomplished with a prolonged fast if symptoms occur in the food-deprived state and with a mixed meal if symptoms are postprandial.

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 Whipple's triad and thereby establish that hypoglycemia is the basis for the patient's symptoms. If Whipple's 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 polypeptides 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 polypeptides 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%.11 Truncation of the fast at 48 hours, if hypoglycemia has not occurred by then, risks misdiagnosis.

Table 2 Protocol for Prolonged Supervised Fast

1. Date the onset of the fast as of the last ingestion of calories. Discontinue all nonessential medications.

2. Allow the patient to drink calorie-free and caffeine-free beverages.

3. Ensure that the patient is active during waking hours.

4. Measure plasma glucose, insulin, C-peptide, proinsulin, and β-hydroxybutyrate in the same specimen. Repeat measurements every 6 hr until the plasma glucose level drops below 60 mg/dl; then repeat the measurements every 1–2 hr.

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, β-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.

6. Feed the patient.

Starting the fast overnight has allowed 40% of patients (including those with insulinoma and other causes of hypoglycemia) 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 Whipple's 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 hypoglycemia. 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. A progressive rise in β-hydroxybutyrate during the fast may indicate a negative fast and preclude taking the fast to 72 hours.13

Beta Cell Polypeptides and Their Surrogates

Concentrations of beta cell polypeptides (i.e., 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 µU/ml or greater; C-peptide, 200 pmol/L or greater; and proinsulin, 5 pmol/L or greater [see Figure 1].14

 

Figure 1. During the 72-hour fast, levels of serum glucose are compared with serum levels of insulin (a), C-peptide (b), proinsulin (c), and β-hydroxybutyrate (d). At the end of the fast, 1 mg of glucagon is injected intravenously, and its effect on glucose levels is measured (e). In normal persons, glucose levels may drop into the hypoglycemic range, so careful documentation of hypoglycemic symptoms is necessary.

Insulin concentrations rarely exceed 100 µU/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 β-hydroxybutyrate can be used as a surrogate for measurement of insulin. The serum β-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].1

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-insulin-mediated hypoglycemia have lesser increases [see Figure 1].14 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 (β-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.

Sulfonylureas and Meglitinides

Persons with hypoglycemia from inappropriate use of sulfonylureas 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 are 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 for 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).14 Very low titers of insulin antibodies may sometimes be detected in persons without hypoglycemia15 and, in rare instances, in patients with insulinomas.

Glycated Hemoglobin

Measurement of glycated hemoglobin is not a standard aspect of the clinical evaluation of hypoglycemia. Concentrations of glycated hemoglobin are statistically significantly lower in patients with insulinomas than in normal persons, but there is too much overlap between the two groups for this test to provide a diagnostic criterion.6

Oral Glucose Tolerance Test

The oral glucose tolerance test should not be used for the evaluation of hypoglycemia, because it is fraught with risk of misdiagnosis. At least 10% of healthy persons have serum glucose nadirs below 50 mg/dl, and the results of the test do not correlate with serum glucose responses to a mixed meal (i.e., a meal containing a balance of proteins, carbohydrates, and fat).

Mixed-Meal Test

For persons with a history of neuroglycopenic symptoms within 5 hours after food ingestion, a mixed-meal test may be conducted. The test is considered to be positive if the patient experiences neuroglycopenic symptoms when a concomitant serum glucose level measures 50 mg/dl or less. A positive mixed-meal test does not provide a diagnosis, only biochemical confirmation of the history.

C-Peptide Suppression Test

C-peptide is formed during the conversion of proinsulin to insulin by the pancreatic beta cells. In the C-peptide suppression test, the patient fasts overnight and then receives an hour-long intravenous infusion of insulin, during which levels of serum glucose and C-peptide are measured. In normal patients, hypoglycemia from the exogenous insulin results in suppression of C-peptide production; patients with insulinomas have higher levels of C-peptide. When the likelihood of a hypoglycemic disorder is not high, a normal result on the C-peptide suppression test may preclude the need for a 72-hour fast. Interpretation of the C-peptide suppression test requires normative data appropriately adjusted for the patient's body mass index and age.7 This test is no longer in common use.

Intravenous Tolbutamide Test

In the past, serum glucose response to an intravenous injection of tolbutamide was used in the diagnosis of insulinoma. This test is potentially dangerous and is less accurate than other tests for insulinoma and, therefore, has been rarely used in recent years.

Conditions That Cause Hypoglycemia

The causes of hypoglycemia in healthy-appearing adults encompass the following conditions: insulinoma, factitious hypoglycemia from insulin or sulfonylurea, NIPHS, and insulin autoimmune hypoglycemia.

Insulinoma

Epidemiology

Between 1927 and 1986, 224 hypoglycemic patients underwent their first pancreatic exploration at the Mayo Clinic and were found to have insulinoma. Because of the relatively large number of cases of insulinoma treated at the Mayo Clinic, in comparison with other medical centers, and the comprehensive epidemiologic database that the Mayo Clinic maintains for Olmsted County, Minnesota, it was possible to determine the population-based incidence of insulinoma, the risk of recurrence, and the survival in patients with insulinoma.16

The median age of the Mayo Clinic insulinoma patients was 47 years, with a range of 8 to 82 years; 59% were female. The incidence in Olmsted County was 4 cases per 1 million person-years. Of the 224 patients, 7.6% had multiple endocrine neoplasia type I (MEN I), and 5.8% had malignant insulinoma. The risk of recurrence was greater in patients with MEN I (21%) than in those without this condition (7%). Over a 45-year period, overall survival of the total cohort was similar to the expected survival (78% versus 81%).

Insulinomas have been found in all races, in pregnant patients, and in patients with type 2 diabetes mellitus. One case of insulinoma in type 1 diabetes mellitus has been reported.17

Diagnosis

Laboratory tests

Insulinoma is characterized by hypoglycemia caused by elevated levels of endogenous insulin. Confirmation of the diagnosis requires exclusion of hypoglycemia from exogenous sources.

Localization

Once a biochemical diagnosis of insulinoma has been made, the next step is localization. Success with the various modalities reflects local skill and experience. Great success has been seen with transabdominal ultrasonography and triple-phase spiral computed tomography. Magnetic resonance imaging and scintigraphy with indium-111 (In-111)-pentetreotide (OctreoScan) have not been useful. Percutaneous transhepatic portal venous sampling has been abandoned even by its former proponents.

In patients whose tumor is not found by ultrasonography or CT, the next step is endoscopic ultrasonography. When all other modalities fail, the clinician may consider the selective arterial calcium stimulation test, which provides a means to both regionalize and confirm endogenous hyperinsulinemia. This test involves serial injections of calcium into the splenic, gastroduodenal, and superior mesenteric arteries. Subsequent doubling of serum insulin concentrations in the right hepatic vein indicates hyperfunctioning beta cells in the part of the pancreas served by that artery.

There is general agreement that the best localization of insulinomas is achieved with intraoperative ultrasonography and careful mobilization and palpation of the pancreas by a surgeon experienced with insulinoma surgery. This approach has seen a 98% success rate in the identification of insulinoma. After localization, these patients proceed directly to surgical removal.

Management

The treatment of choice for insulinomas is surgical removal. Depending on the lesion, the surgery required may range from enucleation of the insulinoma to subtotal pancreatectomy. It is advisable for the surgery to be performed at an institution with expertise in the management of insulinoma.

Medical therapy is less effective than tumor resection, but the former can be used in patients who are not candidates for surgery, who refuse surgery, or whose surgery is unsuccessful. The most effective medication for controlling symptomatic hypoglycemia in these patients is diazoxide, which lowers insulin secretion. Diazoxide is given in divided doses of up to 1,200 mg daily. Side effects include edema, which may require high doses of loop diuretics, and hirsutism. Other medications for insulinomas include verapamil, phenytoin, and octreotide.

Factitious Hypoglycemia

The term factitious (or factitial) has been used in medical parlance to imply covert patient activity. The consideration of such a possibility often changes the patient-physician relationship, leading the physician to feel deceived and the patient to feel mistrusted. However, the pejorative connotation with which factitious illness has been encumbered requires softening, because some patients with factitious disease suffer through no fault of their own.

Epidemiology

Factitious hypoglycemia is more common in women and occurs most often in the third or fourth decade of life. Many of these patients work in health-related occupations.

Factitious hypoglycemia in patients with diabetes is probably more common than the incidence noted in published series.18 Confirmation of the diagnosis in these cases can be very difficult. When deprived of access to hypoglycemic agents, diabetic patients with factitious hypoglycemia become hyperglycemic.

Etiology

Factitious hypoglycemia results from the use of insulin or of drugs that stimulate insulin secretion (i.e., sulfonylureas or meglitinides). The most common form of factitious hypoglycemia is the covert self-administration of a hypoglycemic drug or insulin by a patient without diabetes or the inappropriate manipulation of hypoglycemic drugs or insulin by a patient with diabetes. Less often, a parent may administer a hypoglycemic agent to a child; this is a form of child abuse.19 In all reported cases, the alleged perpetrator was the patient's mother, who had ready access to insulin. Insulin has also been used to attempt suicide or homicide.20

There are increasing numbers of patients who, by taking a prescribed medication in good faith, incur hypoglycemia because a sulfonylurea was mistakenly dispensed.21 In most instances, confusion in dispensing the drug arose because of a similarity in the spelling of the name of the intended medication and that of the sulfonylurea; these mistakes can be identified simply by checking the label on the prescription bottle. In some cases, however, the dispensing error was a result of negligence, and the contents of the bottle do not match the label. On occasion, cases have arisen in which a nondiabetic person mistakenly takes hypoglycemic medication belonging to another member of the household.

Diagnosis

The possibility of factitious hypoglycemia should be considered in every patient undergoing evaluation for a hypoglycemic disorder, especially when the hypoglycemia has a chaotic occurrence—that is, when it has no relation at all to meals or fasting. All medications should be identified; the assistance of a pharmacist is desirable, given the possibility of dispensing error. The practice of searching personal effects and labeling insulin with a traceable substance that can be detected in blood or urine is probably unacceptable in the current climate of patients' rights.

The diagnosis of factitious hypoglycemia can usually be established by measuring serum insulin, sulfonylurea, and C-peptide when the patient is hypoglycemic. If a spontaneous episode of hypoglycemia is not observed, the patient should undergo a 72-hour fast. The results of the fast may be negative, however, should the patient not take the offending agent.

In a patient whose hypoglycemia results from the covert use of a hypoglycemic agent, the agent will be present in the blood. A sensitive method such as liquid chromatography linked to mass spectroscopy should be used for the detection of sulfonylureas and meglitinides.

In insulin-related factitious hypoglycemia, the serum insulin level is high and the C-peptide level is suppressed, usually being close to the lower limit of detection. This observation applies both to nondiabetic patients and to those with type 2 diabetes. Patients with type 1 diabetes are characteristically severely insulin deficient and have low or undetectable serum concentrations of C-peptide. Although the C-peptide values in these patients cannot be further suppressed, confirmation that the values are low during a hypoglycemic episode eliminates any consideration of endogenous hyperinsulinism.

Management

Treatment of factitious hypoglycemia is simple: the patient stops taking the offending medication. The difficulty involved when medication is taken in error is identification of the drug. In the case of deliberate covert use, psychiatric referral is indicated.

Noninsulinoma Pancreatogenous Hypoglycemia Syndrome

NIPHS is a newly designated syndrome with unique clinical, diagnostic, radiologic, surgical, and histologic features.22 The typical case involves an adult who does not have insulinoma but who does have hypoglycemia resulting from postprandial hypersecretion of insulin by pancreatic beta cells.

Epidemiology

Like insulinoma, NIPHS affects patients across a broad age range—16 to 78 years, in one series22—and causes severe neuroglycopenia, with loss of consciousness and, in some cases, generalized seizures. Unlike insulinoma, NIPHS occurs predominantly in males (70%). It is seen at our tertiary medical center at a rate of 20% of that of insulinoma.

Pathophysiology and Pathogenesis

Histologic analysis of pancreatic tissue from patients with NIPHS shows cells budding off ducts, which is best seen by chromogranin A and insulin immunohistochemical staining. Islet cell hypertrophy is also evident. No gross or microscopic tumor has been identified on hematoxylin-eosin-stained sections in any NIPHS patients.

Whether islet hypertrophy, nesidioblastosis, or both are pathogenic in these patients is open to question, as is the case with persistent hyperinsulinemic hypoglycemia of infancy (PHHI). However, a role for some form of diffuse islet cell dysfunction appears well established in these cases. Whatever the pathologic process may be, it is nonfocal, yet it does not necessarily involve the entire pancreas uniformly.

The histologic findings in NIPHS are similar to those in PHHI. Although familial forms of PHHI may be associated with mutations in the Kir6.2and SUR1 genes, analysis of these genes in NIPHS patients has not shown such mutations.23 However, these patients may have common mutations at another, as yet unspecified, locus.

Diagnosis

Clinical manifestations

Symptoms of NIPHS occur primarily in the postprandial state 2 to 4 hours after eating.

Laboratory tests

Patients with NIPHS have low serum glucose levels and elevated serum insulin levels in the postprandial period. Because of the short half-life of insulin, the criteria for hyperinsulinemia used in the fasting state appear to apply in the postprandial state, as long as the low glucose level occurs more than 30 minutes from the peak postprandial insulin level. Supervised 72-hour fasts have shown normal results in patients with NIPHS, whereas a negative 72-hour fast in a patient with insulinoma is a rare occurrence.

The selective arterial calcium stimulation test has shown positive results for patients with NIPHS.24,25 All radiologic localizing studies in patients with NIPHS (i.e., transabdominal ultrasonography, triple-phase CT, celiac axis angiography, and intraoperative ultrasonography) have been negative for insulinoma.

Management

Gradient-guided partial pancreatectomy has been effective in relieving symptoms in patients with NIPHS. The pancreas is resected to the left of the superior mesenteric vein when results of the selective arterial calcium stimulation test are positive only for the splenic artery, and the pancreas is resected to the right of the superior mesenteric vein when the test is positive for an additional artery. Fortunately, gradient-guided debulking of the pancreas can ameliorate the symptoms of NIPHS even in patients whose disease would appear to have involved the whole pancreas. In rats, the mechanism for this effect may be related to decreased insulin secretion, attributed to reduced glucose transporter GLUT2, in remnant pancreas after partial pancreatectomy.26 Unfortunately, in a few NIPHS patients, hypoglycemia recurred after a few symptom-free years.

Insulin Autoimmune Hypoglycemia

Epidemiology

IAH is an extraordinarily rare disorder that is observed primarily, although not exclusively, in persons of Japanese and Korean ethnicity. The disorder may occur at any age. IAH tends to be self-limited in Asians, but it may be persistent in whites. There is no gender predilection. Many patients have an ongoing autoimmune disorder or a history of treatment with a sulfhydryl-containing drug such as antithyroid medication. No patients have had a history of exposure to insulin.15

Pathogenesis

IAH is characterized by the presence of autoantibodies to insulin or the insulin receptor. There is speculation that meal ingestion in these patients may result in the unbinding of insulin from these antibodies. However, measurements of total insulin and free insulin have shown no postprandial alteration in their relative concentrations. The mechanism for the generation of insulin antibodies is unknown but may involve enhanced immunogenicity resulting from an effect of the disulfide bond in drugs with a sulfhydryl component.

Diagnosis

Clinical manifestations

Patients with IAH typically experience postprandial hypoglycemia resulting in neuroglycopenia. The symptomatic severity of IAS appears to vary greatly. Whites may become more seriously debilitated than Asians.

Laboratory tests

Serum insulin levels are markedly elevated in IAH, because the insulin antibodies interfere with this assay. Values can be as high as 1,000 µU/ml. Oddly, C-peptide levels are usually not suppressed. Insulin antibody titers are very high, higher than those seen in insulin-treated diabetic patients. The antibodies may bind only to human insulin or to human, beef, and pork insulin. The antibodies may be polyclonal or monoclonal, and they usually have characteristics similar to those that occur in patients with type 1 diabetes mellitus. It should be noted that very low titers of insulin antibodies may also be observed in healthy persons without hypoglycemia and occasionally in persons with insulinoma.

Management

Supportive treatment, such as frequent small meals, may be effective in IAH, especially for mild cases. For more severely affected patients, a variety of approaches have been tried, including glucocorticoids, immunosuppressants, plasmapheresis, octreotide, and diazoxide. Unfortunately, all these treatments usually fail. Use of partial pancreatectomy and splenectomy has led to amelioration but not complete resolution of symptoms.

Post-Gastric Bypass Hypoglycemia

Patients who have undergone Roux-en-Y gastric bypass, whether for medically complicated obesity or other reasons, have a propensity to experience hypoglycemia.27

Epidemiology

This disorder appears to occur more often in women. Its true incidence is unknown. At our tertiary center, the current rate of identification is several-fold greater than that of insulinoma.

Pathophysiology

It has been speculated that gastric bypass may lead to increased secretion of gastrointestinal hormones that stimulate insulin release (incretins), such as glucagonlike peptide-1 (GLP-1). In turn, increased levels of GLP-1 and other incretins may result in pancreatic islet hypertrophy.

Diagnosis

Most patients with post-gastric bypass hypoglycemia have postprandial hypoglycemia. The evaluation is similar to that of patients with NIPHS. However, some patients have pre-existing insulinoma, which likely led to overeating, obesity, and, ultimately, bariatric surgery. Such patients develop hypoglycemia in the fasting state.

Laboratory Tests

These patients have endogenous hyperinsulinemic hypoglycemia. The diagnostic criteria are the same as for NIPHS or insulinoma.

Management

For severely affected patients with nesidioblastosis, the best chance for amelioration is gradient guided partial pancreatectomy. For patients with insulinoma, enucleation or partial pancreatectomy is appropropriate. In some patients, lifestyle change or the use of acarbose or octreotide has provided control of symptoms.

References

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  2. Macaron CI, Kadri A, Macaron Z: Nucleated red blood cells and artifactual hypoglycemia. Diabetes Care 4:113, 1981
  3. Service FJ, Veneziale CM, Nelson RA et al: Combined deficiency of glucose-6-phosphate and fructose-1,6-diphosphate: studies of glucagon secretion and fuel utilization. Am J Med 64:698, 1978
  4. Hepburn DA, Deary IJ, Frier BM et al: Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM: factor-analysis approach. Diabetes Care 14:949, 1991
  5. Service FJ, Dale AJ, Elveback LR et al: Insulinoma: clinical and diagnostic features of 60 consecutive cases. Mayo Clin Proc 51:417, 1976
  6. Hassoun AA, Service FJ, O'Brien PC: Glycated hemoglobin in insulinoma. Endocr Pract 4:181, 1998
  7. Service FJ, O'Brien PC, Kao PC et al: C-peptide suppression test: effects of gender, age and body mass index: implications for the diagnosis of insulinoma. J Clin Endocrinol Metab 74:204, 1992
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  16. Service FJ, McMahon MM, O'Brien PC et al: Functioning insulinoma: incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clin Proc 66:711, 1991
  17. Svartberg J, Stridsberg M, Wilander E et al: Tumour-induced hypoglycaemia in a patient with insulin-dependent diabetes mellitus. J Intern Med 239:181, 1996
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  22. Service FJ, Natt N, Thompson GB et al: Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2and SUR1 genes. J Clin Endocrinol Metab 84:1582, 1999
  23. Thomas PM, Cote GJ, Wohlik N et al: Mutations in the sulfonylurea receptor gene in familial hyperinsulinemic hypoglycemia of infancy. Science 268:426, 1995
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  25. O'Shea D, Rohrer-Theus A, Lynn JA et al: Localization of insulinomas by selective intraarterial calcium injection. J Clin Endocrinol Metab 81:1623, 1996
  26. Zangen DH, Bonner-Weir S, Lee CH et al: Reduced insulin, GLUT2, and IDX-1 in beta-cells after partial pancreatectomy. Diabetes 46:258, 1997
  27. Service GJ, Thompson GB, Service FJ et al: Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med 353:249, 2005

Editors: Dale, David C.; Federman, Daniel D.