Specific Hypoglycemic Disorders
Iatrogenic hypoglycemia is common in type 1 patients and also in insulin treated type 2 patients. Most type 1 patients aiming for HbA1c levels below 7% have on average one to two symptomatic hypoglycemic episodes per year. Severe hypoglycemia is defined as an episode requiring assistance, and in one study, incidence rates were about 12 per 100 patient years for both type 1 and insulin-treated type 2 patients. Sulfonylureas, repaglinide, and nateglinide can also cause hypoglycemia. Increased risk factors include age (70 years and older), renal failure, hepatic failure, and use of the long-acting sulfonylureas. A number of other drug-drug interactions (clarithromycin, salicylates, sulfonamides) can also potentiate the hypoglycemic effects of sulfonylureas. The annual incidence of sulfonylurea-induced hypoglycemia is approximately 0.2 per 1000 patient years.
As β cell failure progresses (early in type 1 and late in type 2 diabetes), patients lose their glucagon response to hypoglycemia. This combination of insulin deficiency and impaired glucagon response makes it harder for patients to achieve HbA1c levels below 7% without occasional hypoglycemia. These hypoglycemic episodes attenuate the sympathoadrenal response to hypoglycemia, with decreased epinephrine release from the adrenal and decreased sympathetic neural responses (hypoglycemic unawareness). The hypoglycemia unawareness in turn increases the risk for recurrent hypoglycemia. About 20% to 25% of type 1 patients have hypoglycemic unawareness. Other factors that increase the risk for hypoglycemia include poor self-management skills. Patients may take too much insulin for the carbohydrates or take the wrong insulin or do not appropriately time insulin administration with food ingestion. They also may not adjust the insulin for acute exercise or take extra carbohydrates for unexpected exercise or reduce insulin doses for improved insulin sensitivity with exercise training. Alcohol can decrease endogenous glucose production and can cause hypoglycemia, especially if it is consumed on an empty stomach. Diabetes complications—gastroparesis, autonomic neuropathy, and renal failure also increase the risk for hypoglycemia.
There are other consequences of hypoglycemia apart from the autonomic and neurogenic symptoms of acute hypoglycemia. In severe cases, hypoglycemia can cause convulsions and coma. Permanent neurological damage is rare. Although cross-sectional studies and case reports have reported intellectual decline with recurrent hypoglycemia, longitudinal studies have not shown significant cognitive dysfunction in adults. In the Diabetes Control and Complications Trial, there was no evidence for cognitive decline related to hypoglycemia in 18 years of follow-up. Young children however may be more vulnerable to the effects of hypoglycemia on the brain. Hypoglycemia via its autonomic stimulation and catecholamine release increases cardiac output. In patients with cardiac disease it can also precipitate cardiac arrhythmias, angina, myocardial infarction, and congestive heart failure.
Hypoglycemia can also exert a psychological toll. Acute hypoglycemia induces mood changes including fatigue, pessimism, anger, and behavior changes. Nocturnal hypoglycemia can lead to fatigue and decreased sense of well being the following day. Patients who have had severe hypoglycemia may develop a phobia about hypoglycemia and keep their sugars unreasonably high. Some patients develop an anxiety syndrome. Hypoglycemia can also impact personal relationships, occupation, driving, and leisure activities. Surveys show that type 1 patients have increased risk of driving mishaps (crashes, moving violations) when compared to nondiabetic spouses; and that these are related to hypoglycemia.
The goal of therapy is to restore levels of plasma glucose to normal as rapidly as possible. If the patient is conscious and able to swallow, glucose-containing foods such as candy, orange juice with added sugar, and cookies should be quickly ingested. Fructose, found in many nutrient low-calorie sweeteners for diabetics, should not be used. While it can be metabolized by neurons, fructose is not transported across the blood–brain barrier.
If the patient is unconscious, rapid restoration of plasma glucose must be accomplished by giving 20 to 50 mL of 50% dextrose intravenously over 1 to 3 minutes (the treatment of choice) or, when intravenous glucose is not available, 1 mg of glucagon intramuscularly or intravenously. Families or friends of insulin-treated diabetics should be instructed in the administration of glucagon intramuscularly for emergency treatment at home. Glucagon should not be given if the hypoglycemia is due to sulfonylurea use. Under these circumstances, glucagon can stimulate insulin secretion and worsen the hypoglycemia. Attempts to feed the patient or to apply glucose-containing jelly to the oral mucosa should be avoided because of the danger of aspiration. When consciousness is restored, oral feedings should be started immediately. In patients who have taken massive overdoses of sulfonylureas, the response to intravenous dextrose may be poor. For these patients, intravenous boluses of diazoxide (150-300 mg) may be tried but can result in hypotension. Intravenous octreotide (100 μg) has also been reported to be of benefit.
Patients on insulin or sulfonylureas should be instructed on how to recognize and treat hypoglycemia and what measures they can take to prevent such episodes. Type 1 patients and insulin-treated type 2 patients should monitor their blood glucose frequently. Hypoglycemia not infrequently occurs at night and patients should avoid taking large doses of short-acting insulin just before going to bed. Patients should from time to time also monitor blood glucose levels in the middle of the night. Hypoglycemia can also occur many hours after strenuous exercise, and patients should be advised to monitor at these times and cut back their insulin doses and/or eat more carbohydrate. Continuous glucose monitoring systems are increasingly used by type 1 patients to alert them to falling glucose levels and prevent hypoglycemia. Finally, it is important to individualize glycemic goals. Early in the course of both type 1 and type 2 diabetes when there is still some endogenous β cell function, it is easier to achieve HbA1c levels close to normal with low risk of hypoglycemia. As β cell failure progresses, however, aiming for normality may lead to unacceptably high rates of hypoglycemia. Patients who have had frequent hypoglycemia and have hypoglycemia unawareness should be encouraged to temporarily raise their glycemic targets—as little as 2 to 3 weeks of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the attenuated epinephrine response. Diabetes complications, previous incidence of hypoglycemia, and life expectancy should all be considered in the establishment of glycemic goals.
Factitious hypoglycemia should be suspected in any patient with access to insulin or sulfonylurea drugs. It is most commonly seen in health professionals and diabetic patients or their relatives. The reasons for self-induced hypoglycemia vary, with many patients having severe psychiatric disturbances or a pathological need for attention. Inadvertent ingestion of sulfonylureas resulting in clinical hypoglycemia has also been reported, due either to patient error or to a prescription mishap on the part of a pharmacist. Patients with diabetes and factitious hypoglycemia have a presentation similar to brittle diabetes.
When insulin is used to induce hypoglycemia, an elevated serum insulin level often raises suspicion of an insulin-producing pancreatic β cell tumor. It may be difficult to prove that the insulin is of exogenous origin. The combination of hypoglycemia, high immunoreactive insulin levels, suppressed plasma C peptide, and suppressed proinsulin level is pathognomonic of exogenous insulin administration in nondiabetic patients. Patients with renal failure may have normal or even high plasma C-peptide levels, but plasma proinsulin levels are suppressed.
When sulfonylurea abuse is suspected, plasma or urine should be screened for its presence. Hypoglycemia with inappropriately elevated levels of serum insulin and C peptide along with detectable sulfonylureas in blood or urine is diagnostic of inadvertent or factitious sulfonylurea overdose. It is important to use assays which measure not only all the sulfonylureas but also repaglinide and nateglinide.
Treatment of factitious hypoglycemia involves psychiatric therapy and social counseling.
Numerous pharmacologic agents may potentiate the effects of insulin and predispose to hypoglycemia. Common offenders include fluoroquinolones such as gatifloxacin and levofloxacin, pentamidine, quinine, angiotensin-converting enzyme (ACE) inhibitors, ethanol, salicylates, and beta-adrenergic–blocking drugs. The fluoroquinolones, especially gatifloxacillin, have been associated with both hypoglycemia and hyperglycemia. Hypoglycemia is an early event; hyperglycemia occurs after several days into therapy. It is thought that the drugs act on ATP-sensitive potassium channels in the β cell. Intravenous pentamidine is cytotoxic to pancreatic β cells, resulting in acute insulin release and hypoglycemia. This occurs in about 10% to 20% of patients receiving the drug and may be followed later by persistent insulinopenia and hyperglycemia. Fasting patients taking noncardioselective beta blockade can have an exaggerated hypoglycemic response to starvation. Beta blockade inhibits fatty acid and gluconeogenic substrate release and reduces plasma glucagon levels resulting in hypoglycemia. Also the symptomatic response to hypoglycemia is altered—tachycardia is blocked while hazardous elevations of blood pressure may result during hypoglycemia in response to the unopposed alpha-adrenergic stimulation from circulating catecholamines and neurogenic sympathetic discharge. However, symptoms of sweating, hunger, and uneasiness are not masked by beta-blocking drugs and remain indicators of hypoglycemia in the aware patient.
Therapy with ACE inhibitors increases the risk of hypoglycemia in diabetic patients who are taking insulin or sulfonylureas, presumably because these drugs increase sensitivity to circulating insulin by increasing blood flow to muscle.
Ethanol-associated hypoglycemia has been proposed to occur as a consequence of hepatic alcohol dehydrogenase activity depleting NADH. The resultant change in the redox state (NADH-to-NAD+ ratio) limits the conversion of lactate to pyruvate, the main substrate for hepatic gluconeogenesis. In the patient who is imbibing ethanol but not eating, fasting hypoglycemia may occur after hepatic glycogen stores have been depleted (within 8-12 hours of a fast). No correlation exists between the blood ethanol levels and the degree of hypoglycemia, which may occur while blood ethanol levels are declining. It should be noted that ethanol-induced fasting hypoglycemia may occur at ethanol levels as low as 45 mg/dL (10 mmol/L)—considerably below most states' legal standards (80 mg/dL [17.4 mmol/L]) for being under the influence. Most patients present with neuroglycopenic symptoms, which may be difficult to differentiate from the neurotoxic effects of the alcohol. These symptoms in a patient whose breath smells of alcohol may be mistaken for alcoholic stupor. Intravenous dextrose should be administered promptly to all such stuporous or comatose patients. Because hepatic glycogen stores have been depleted by the time hypoglycemia occurs, parenteral glucagon is not effective. Adequate food intake during alcohol ingestion prevents this type of hypoglycemia.
In recent years, a rare autoimmune disorder has been reported in which patients have circulating insulin antibodies and the paradoxic feature of hypoglycemia. More than 200 cases of insulin-antibody-associated hypoglycemia have been reported since 1970, with 90% of cases reported in Japanese patients. HLA class II alleles (DRB1*0406, DQA1*0301, and DQB1*0302) are associated with this syndrome, and these alleles are 10 to 30 times more prevalent in Japanese and Koreans, which may explain the higher prevalence of this syndrome in these populations. Hypoglycemia generally occurs 3 to 4 hours after a meal and follows an early postprandial hyperglycemia. It is attributed to a dissociation of insulin-antibody immune complexes, releasing free insulin. This autoimmune hypoglycemia, which is due to accumulation of high titers of antibodies capable of reacting with endogenous insulin, has been most commonly reported in methimazole-treated patients with Graves disease from Japan as well as in patients with various other sulfhydryl-containing medications (captopril, penicillamine) and other drugs such as hydralazine, isoniazid, and procainamide. In addition, it has been reported in patients with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and polymyositis, as well as in multiple myeloma and other plasma cell dyscrasias where paraproteins or antibodies cross-react with insulin.
High titers of insulin autoantibodies, usually IgG class, can be detected. Insulin, proinsulin, and C-peptide levels may be elevated but the results may be erroneous because of the interference of the insulin antibodies with the immunoassays for these peptides.
In most cases the hypoglycemia is transient and usually resolves spontaneously within 3 to 6 months of diagnosis, particularly when the offending medications are stopped. The most consistent therapeutic benefit in management of this syndrome has been achieved by dietary treatment with frequent, low-carbohydrate, small meals. Prednisone therapy (30-60 mg/d) has been used to lower the titer of insulin antibodies.
Hypoglycemia due to insulin receptor autoantibodies is also an extremely rare syndrome; most cases have occurred in women often with a history of autoimmune disease. Almost all of these patients have also had episodes of insulin-resistant diabetes and acanthosis nigricans. Their hypoglycemia may be either fasting or postprandial and is often severe and is attributed to an agonistic action of the antibody on the insulin receptor. Balance between the antagonistic and agonistic effects of the antibodies determines whether insulin-resistant diabetes or hypoglycemia occurs. Hypoglycemia was found to respond to glucocorticoid therapy but not to plasmapheresis or immunosuppression.
Spontaneous fasting hypoglycemia in an otherwise healthy adult is most commonly due to insulinoma, an insulin-secreting tumor of the islets of Langerhans. Eighty percent of these tumors are single and benign; 10% are malignant (if metastases are identified); and the remainder are multiple, with scattered micro- or macroadenomas interspersed within normal islet tissue. (As with some other endocrine tumors, histologic differentiation between benign and malignant cells is difficult, and close follow-up is necessary to ensure the absence of metastases.)
These adenomas may be familial and have been found in conjunction with tumors of the parathyroid glands and the pituitary (multiple endocrine neoplasia type 1; see Chapter 22). Over 99% of them are located within the pancreas and less than 1% in ectopic pancreatic tissue.
These tumors may appear at any age, although they are most common in the fourth to sixth decades. A slight predominance in women has been reported in some studies. However, others suggest that there is no gender predilection.
The signs and symptoms are chiefly those of subacute or chronic neuroglycopenia rather than adrenergic discharge. The typical picture is that of recurrent central nervous system dysfunction at times of exercise or fasting. Symptoms include episodic disorientation, somnolence, personality changes, amnesia, and loss of consciousness. The preponderance of neuroglycopenic symptoms, rather than those more commonly associated with hypoglycemia (adrenergic symptoms), often leads to delayed diagnosis following prolonged psychiatric care, or treatment for seizure disorders or transient ischemic attacks. Some patients learn to relieve or prevent their symptoms by taking frequent feedings. Obesity may be the result; however, obesity is seen in less than 30% of patients with insulin-secreting tumors.
Experts in this field emphasize that the most important prerequisite to diagnosing an insulinoma is simply to consider it, particularly when facing a clinical presentation of fasting hypoglycemia with symptoms of central nervous system dysfunction such as confusion or abnormal behavior. Whipple triad consists of history of symptoms consistent with hypoglycemia, associated low plasma glucose and relief of symptoms upon raising the plasma glucose. β cell tumors do not demonstrate suppression of insulin secretion in the presence of hypoglycemia, and a serum insulin level of 6 μU/mL or more with concomitant plasma glucose values below 45 mg/dL (2.5 mmol/L) suggests an insulinoma. Other causes of hyperinsulinemic hypoglycemia must be considered, however, such as surreptitious administration of insulin or sulfonylureas.
One of the most important steps is to carefully review the patient's history. Attention should be paid to the nature of the symptoms and factors that precipitate and resolve the symptoms. Patients typically complain of feeling tired, experiencing blurred vision, and not thinking clearly. Eating or drinking readily absorbable carbohydrates improves the symptoms within approximately 15 minutes. Timing of the symptoms in relation to meals and exercise should be noted. In insulinoma patients, the symptoms are most likely to occur early in the morning before breakfast or if a meal is missed during the day. Patients occasionally present when they attempt to go on a diet to lose weight. Exercise may precipitate the symptoms especially if the activity occurs while fasting or some hours after a meal. Some patients develop symptoms in the middle of the night and may have to eat. Partners of patients often provide useful information, especially if the patient requires assistance in treating the hypoglycemic symptoms. Occasionally the emergency services are called when the patient gets severely confused, presents with focal weakness, loses consciousness, or has a seizure. There may be documentation of low fingerstick glucose at the time when symptoms are present with recovery following administration of intravenous glucose. With the ready availability of home blood glucose–monitoring systems, patients sometimes present with documented fingerstick blood glucose levels in 40s and 50s at time of symptoms. Access to diabetic medications (sulfonylureas or insulin) should be explored—does a family member have diabetes or does the patient or family member work in the medical field? Medication-dispensing errors should be excluded—has the patient's prescription medication changed in shape or color? Other illnesses that cause hypoglycemia such as renal failure, hepatic failure, Addison disease, or nonislet tumor should be considered. Patients with insulinoma or factitious hypoglycemia usually have a normal physical examination.
If the history is consistent with episodic spontaneous hypoglycemia, patients should be given a home blood glucose monitor and advised to monitor blood glucose levels at the time of symptoms if it is safe and before consumption of carbohydrates. Patients with insulinomas frequently will report fingerstick blood glucose levels in the 40s at the time of symptoms. The diagnosis, however, cannot be made based on a fingerstick blood glucose. It is necessary to have a low laboratory glucose concomitantly with elevated plasma insulin, proinsulin and C-peptide levels, and a negative sulfonylurea screen. When patients give a history of symptoms after only a short period of food withdrawal or with exercise, then an outpatient assessment can be attempted. The patient should be brought by a family member to the office after an overnight fast and observed in the office. Activity such as walking should be encouraged and fingerstick blood glucose measured repeatedly during observation. If symptoms occur or fingerstick blood glucose is below 50 then samples for plasma glucose, insulin, C peptide, proinsulin, sulfonylurea screen, serum ketones, and antibodies to insulin should be sent. If outpatient observation does not result in symptoms or hypoglycemia and if the clinical suspicion remains high, then the patient should undergo an inpatient, supervised, 72-hour fast.
A suggested protocol for the supervised fast is set forth in Table 18–4. In normal men, the blood glucose value does not fall below 55 mg/dL (3.1 mmol/L) during a 72-hour fast, whereas insulin levels fall below 10 μU/mL; in some normal women, however, plasma glucose may fall below 30 mg/dL (1.7 mmol/L) (lower limits have not been established), but serum insulin levels also fall appropriately to less than 5 μU/mL. These women remain asymptomatic despite this degree of hypoglycemia, presumably because ketogenesis is able to provide sufficient fuel for maintenance of central nervous system function. The fast is timed from the last intake of calories. The term 72-hour fast is actually a misnomer in most cases, because the fast should be immediately terminated as soon as symptoms and laboratory confirmation of hypoglycemia are evident. About 43% of patients with insulinomas are symptomatic within the first 12 hours, 67% by 24 hours and 93% to 95% by 48 hours. Since a minority of patients (∼5%-7%) may not demonstrate hypoglycemia after 48 hours of fasting, it is preferable to continue the fast for up to 72 hours. Patients can drink water and decaffeinated, noncaloric drinks. It is important that patients are active (walking) during the fast since exercise may help precipitate hypoglycemia. An intravenous cannula should be placed to allow for blood draws and as a safety precaution, should intravenous dextrose infusion be required. Fingerstick blood glucose levels should be measured at intervals and blood sent to the laboratory if the patient is symptomatic or when fingerstick blood glucose levels are below 50 mg/dL. The decision to stop the fast is not always easy. Patients should be carefully monitored for symptoms of hypoglycemia. If the patient is symptomatic and the laboratory glucose is less than 45 mg/dL then the test can be stopped. If the symptoms are equivocal and the laboratory glucose is in the mid 50s or higher, then the fast should be continued, if the patient is agreeable. At the time of termination of the fast, blood should be sent to the laboratory for plasma glucose, insulin, proinsulin, C peptide, and serum β-hydoxybutyrate levels and a sulfonylurea screen.
Table 18–4 Suggested Hospital Protocol for Supervised Rapid Diagnosis of Insulinoma. ||Download (.pdf)
Table 18–4 Suggested Hospital Protocol for Supervised Rapid Diagnosis of Insulinoma.
|(1) Obtain baseline serum glucose, insulin, proinsulin, and C-peptide measurements at onset of fast and place intravenous cannula.|
|(2) Permit only calorie-free and caffeine-free fluids and encourage supervised activity (such as walking).|
|(3) Measure urine for ketones at the beginning and every 12 hours and at end of fast.|
|(4) Obtain capillary glucose measurements with a reflectance meter every 4 hours until values <60 mg/dL are obtained. Then increase the frequency of fingersticks to each hour, and when capillary glucose value is <49 mg/dL, send a venous blood sample to the laboratory for serum glucose, insulin, proinsulin, and C-peptide measurements. Check frequently for manifestations of neuroglycopenia.|
|(5) If symptoms of hypoglycemia occur or if a laboratory value of serum glucose is <45 mg/dL or if 72 hours have elapsed, then conclude the fast with a final blood sample for serum glucose, insulin, proinsulin, C-peptide, β-hydroxybutyrate or acetone, and sulfonylurea measurements. Then give oral fast-acting carbohydrate followed by a meal. If the patient is confused or unable to take oral agents, administer 50 mL of 50% dextrose intravenously over 3-5 minutes. Do not conclude a fast based simply on basis of a capillary blood glucose measurement—wait for the laboratory glucose value unless the patient is symptomatic and it would be dangerous to wait.|
Virtually all patients with insulin-secreting islet cell tumors fail to suppress their insulin secretion appropriately when the plasma glucose is less than 45 mg/dL (Table 18–5). It is important to be aware of limitations of the particular insulin assay that is used. When radioimmunoassays (RIAs) with a sensitivity of 5 μU/mL are used, patients with insulinomas have plasma insulin concentrations of 6 μU/mL or more. Immunochemiluminometric assays (ICMA) have sensitivities of less than 1 μU/mL, and with these assays, the cutoff for insulinomas is 3 μU/mL or higher. Previous treatment with insulin may lead to development of autoantibodies to insulin that interfere with the assays, leading to falsely low or elevated values depending on the method used. Proper collection of samples is also important. If serum is not separated and frozen within 1 to 2 hours, falsely low values result because the insulin molecule undergoes proteolytic degradation. Plasma insulin levels measured by ICMA may be lower in hemolyzed samples. Calculation of ratios of insulin (μU/mL) to plasma glucose (mg/dL) is not helpful in making the diagnosis.
Table 18–5 Diagnostic Criteria for Insulinoma after a 72-Hour Fast. ||Download (.pdf)
Table 18–5 Diagnostic Criteria for Insulinoma after a 72-Hour Fast.
|Plasma insulin (RIA)||≥6 uU/mL|
|Plasma insulin (ICMA)||≥3 uU/mL|
|Plasma C peptide||≥200 pmol/L|
|Plasma proinsulin||≥5 pmol/L|
|Sulfonylurea screen (including repaglinide and nateglidine)||Negative|
Factitious use of insulin will result in suppression of endogenous insulin secretion and low C-peptide levels. Elevated circulating proinsulin levels in the presence of fasting hypoglycemia is characteristic of most β cell tumors and does not occur in factitious hyperinsulinism. Thus, C-peptide and proinsulin levels (by ICMA) of ≥200 pmol/L and ≥5 pmol/L, respectively, are characteristic of insulinomas. C peptide is renally cleared and caution should be used in interpreting elevated levels in the setting of renal failure. Proinsulin normally represents less than 10% of total immunoreactive insulin. Insulinoma cells are poorly differentiated, which affects their ability to process proinsulin to insulin. Thus, most patients with insulinoma have elevated levels of proinsulin, representing as much as 30% to 90% of total immunoreactive insulin. Hyperinsulinemia suppresses ketone production. Plasma β-hydroxybutyrate levels in patients with insulinoma are 2.7 nmol/L or less. A progressive increase in β-hydroxybutyrate levels after 18 hours of fasting is strongly predictive that the fast will be negative.
A variety of stimulation tests with intravenous tolbutamide, glucagon, or calcium have been devised to demonstrate exaggerated and prolonged insulin secretion in the presence of insulinomas. However, because insulin-secreting tumors have a wide range of granule content and degrees of differentiation, they are variably responsive to these secretagogues. Thus, absence of an excessive insulin-secretory response during any of these stimulation tests does not rule out the presence of an insulinoma. In addition, the tolbutamide stimulation test is extremely hazardous to patients with responsive tumors because it induces prolonged and refractory hypoglycemia. For that reason, it is no longer included in the diagnostic workup of insulinoma.
The hyperinsulinism associated with insulinoma impairs glycogenolysis. Thus, when patients with insulinoma are given 1 mg IV glucagon at the end of the 72-hour fast, there is an increase in plasma glucose within the first 30 minutes. The glucose rise is 25 mg/dL or more at 20 to 30 minutes, whereas normal subjects have a lower increment. Intravenous glucagon can also cause an exaggerated release of insulin from insulinomas. Patients are tested after an overnight fast, and serum insulin levels measured every 5 minutes for 15 minutes after 1 mg IV glucagon. An increase in insulin level exceeding 130 μU/mL (twice upper limit of normal) suggests an insulin-secreting tumor. However, only about half of patients with insulinomas have insulin levels above 130 μU/mL and so the test is not so helpful. Also, in some patients the exaggerated insulin secretion can lead to severe hypoglycemia. Nausea is an unpleasant side effect, often occurring several minutes after administration of intravenous glucagon.
The oral glucose tolerance test is of no value in the diagnosis of insulin-secreting tumors. A common misconception is that patients with insulinomas have flat glucose tolerance curves because the tumors discharge insulin in response to oral glucose. In fact, most insulinomas respond poorly, and curves typical of diabetes are more common. In those rare tumors that do release insulin in response to glucose, a flat curve may result; however, this also can be seen occasionally in normal subjects.
Low HbA1c values have been reported in patients with insulinoma, reflecting the presence of chronic hypoglycemia. There is however considerable overlap with normal patients and no HbA1c value is diagnostic.
Tumor Localization Studies
After the diagnosis of insulinoma has been unequivocally made by clinical and laboratory findings, studies to localize the tumor should be initiated. The focus of attention should be directed at the pancreas only, because virtually all insulinomas originate from this tissue; ectopic cancers secreting insulin are unknown to all major centers, with only one published report describing an atypical insulin-producing tumor believed to have originated from a small cell carcinoma of the cervix.
Because of the small size of these tumors (average diameter of 1.5 cm in one large series), imaging studies do not necessarily identify all tumors. A pancreatic dual phase, thin section, helical CT scan can identify 82% to 94% of the lesions. MRI scans with gadolinium can be helpful in detecting a tumor in 85% of cases. One case report suggests that diffusion-weighted MRI can be useful for detecting and localizing small insulinomas, especially those with no hypervascular pattern. The imaging study used will depend upon local availability and local radiologic skill. If the imaging study is negative, then an endoscopic ultrasound should be performed. In experienced hands, about 80% to 90% of tumors can be detected. Finally, needle aspiration of the identified lesion can be attempted to confirm the presence of a neuroendocrine tumor. If the tumor is not identified or imaging results are equivocal, then the patient should undergo selective calcium-stimulated angiography which has been reported to localize the tumor to particular regions of the pancreas approximately 90% of the time. In this test, angiography is combined with injections of calcium gluconate into the gastroduodenal, splenic, and superior mesenteric arteries and insulin levels are measured in the hepatic vein effluent. The procedure is performed after an overnight fast. Ten percent of calcium gluconate, diluted to a volume of 5 mL normal saline, is bolused into selected arteries at a dose of 0.0125 mmol Ca2+/kg (0.005 mmol/kg for obese patients). Five milliliter blood samples are taken from the hepatic effluent at times 0, 30, 60, 90, 120, and 180 seconds after calcium injection. Fingerstick blood glucose levels are measured at intervals and a dextrose infusion is maintained throughout the procedure. Calcium stimulates insulin release from insulinomas but not normal islets. A step-up in insulin levels at 30 or 60 seconds (twofold or greater) regionalizes the source of the hyperinsulinism to the head of the pancreas for the gastroduodenal artery, the uncinate process for the superior mesenteric artery, and the body and tail of the pancreas for the splenic artery. A less than twofold elevation of insulin in the 120 second sample may represent effects of recirculating calcium and is not considered a positive localization. In a single insulinoma, the response is in one artery alone (Figure 18–3) unless the tumor resides in an area fed by two arteries or if there are multiple insulinomas as in multiple endocrine neoplasia, type 1. Patients who have diffuse islet hyperplasia (the noninsulinoma pancreatogenous hypoglycemia syndrome [NIPHS]) will have positive responses in multiple arteries. Because diazoxide may interfere with this test, it should be discontinued for at least 48 to 72 hours before sampling. Patients should be closely monitored during the procedure to avoid hypoglycemia (as well as hyperglycemia), which could affect insulin gradients. These studies combined with careful intraoperative ultrasonography and palpation by a surgeon experienced in insulinoma surgery correctly identify up to 98% of tumors.
Responses of serum insulin to selective intra-arterial calcium stimulation in a patient with biochemical confirmation of inappropriate hyperinsulinism. An islet cell tumor was removed from the tail of the pancreas.
The treatment of choice for insulin-secreting tumors is surgical resection. While waiting for surgery, patients should be given diazoxide, a potent inhibitor of insulin secretion. It acts by opening the ATP-sensitive potassium channel of the pancreatic β cell and hyperpolarizing the cell membrane. This reduces calcium influx through the voltage-gated calcium channel, thereby reducing insulin release. Divided doses of 300 to 400 mg/d usually suffice, but occasionally a patient may require up to 800 mg/d. A liquid preparation of diazoxide (50 mg/mL) is available in the United States. Side effects include edema due to sodium retention (which generally necessitates concomitant thiazide administration), gastric irritation, and mild hirsutism.
Tumor resection should be performed only by surgeons with extensive experience with removal of islet cell tumors, because these tumors may be small and difficult to recognize. The tumors are enucleated whenever possible unless they have malignant features (eg, hardness or an appearance of infiltration). Preoperative imaging studies, including endoscopic ultrasound, can identify tumors amenable to laparoscopic surgery. Laparoscopic surgery is associated with faster postoperative recovery. Laparoscopic intraoperative ultrasound should be used to confirm the location and depth of the tumor within the gland and also note its relationship to the pancreatic duct and splenic vessels. Open surgery is still necessary for some tumors such as those in the head of the pancreas close to the main pancreatic duct. In the very occasional case where the tumor cannot be found at operation despite the use of intraoperative ultrasound, it is no longer advisable to blindly resect the body and tail of the pancreas since a nonpalpable tumor, missed by ultrasound, is most likely embedded within the fleshy head of the pancreas that is left behind with subtotal resections. Most surgeons prefer to close the incision and treat the patient medically and/or repeat the localization studies.
Diazoxide should be administered on the day of surgery in patients who are responsive to it, because the drug greatly reduces the need for glucose supplements and the risk of hypoglycemia during surgery. Typically, it does not mask the glycemic rise indicative of surgical cure. Blood glucose levels should be monitored frequently during the operation and a 5% or 10% dextrose infusion should be used to maintain euglycemia. Hyperglycemia occurs for a few days postoperatively most likely due to edema and inflammation of the pancreas secondary to its mobilization and manipulation during surgical resection of the insulinoma. However, other possible contributing factors include high levels of counterregulatory hormones induced by the procedure, chronic downregulation of insulin receptors by the previously high circulating insulin levels from the tumor, and, perhaps, suppression of normal pancreatic β cells by long-standing hypoglycemia. Small subcutaneous doses of regular insulin may be prescribed every 4 to 6 hours if plasma glucose exceeds 300 mg/dL (16.7 mmol/L), but in most cases pancreatic insulin secretion recovers after 48 to 72 hours, and very little insulin replacement is required.
Diazoxide therapy is the treatment of choice in patients with inoperable functioning islet cell carcinomas and in those who are poor candidates for operation. A few patients have been maintained on long-term (>10 years) diazoxide therapy with no apparent ill effects. Hydrochlorothiazide, 25 to 50 mg daily, should also be prescribed to counteract the edema and hyperkalemia secondary to diazoxide therapy as well as to potentiate its hyperglycemic effect. Frequent carbohydrate feedings (every 2-3 hours) can also be helpful in maintaining euglycemia, although obesity may become a problem.
When patients are unable to tolerate diazoxide because of side effects such as gastrointestinal upset, hirsutism, or edema, a calcium channel blocker such as verapamil (80 mg given orally every 8 hours) may be tried. This is based, in part, on verapamil's inhibitory effect on insulin release from insulinoma cells in vitro.
A potent long-acting synthetic octapeptide analog of somatostatin (octreotide) has been used to inhibit release of hormones from a number of endocrine tumors, including inoperable insulinomas, but it has had limited success with the latter. Of the five somatostatin receptors (SSTRs) that have been identified in humans, SSTR2, which predominates in the anterior pituitary, has a much greater affinity for octreotide than SSTR5, which predominates in the pancreas. This explains why octreotide is much more effective in treating acromegaly than in treating insulinoma, except in the occasional cases where insulinoma cells happen also to express SSTR2. When hypoglycemia persists after attempted surgical removal of the insulinoma and if diazoxide or verapamil is poorly tolerated or ineffective, a trial of 50 μg of octreotide injected subcutaneously twice daily may control the hypoglycemic episodes in conjunction with multiple small carbohydrate feedings.
Streptozocin has proved to be beneficial in patients with islet cell carcinomas. With selective arterial administration, effective cytotoxic doses have been achieved without the undue renal toxicity that characterized early experience. Benign tumors appear to respond poorly, if at all.
Nonislet Cell Tumor Hypoglycemia (Nicth)
A variety of nonislet cell tumors have been found to cause fasting hypoglycemia. Most are large and mesenchymal in origin, retroperitoneal fibrosarcoma being the classic prototype. However, hepatocellular carcinomas, adrenocortical carcinomas, renal cell carcinomas, gastrointestinal tumors, lymphomas, leukemias, and a variety of other tumors have also been reported.
Laboratory diagnosis depends on fasting hypoglycemia associated with serum insulin levels below 5 μU/mL. In many cases, the hypoglycemia is due to the expression and release of an incompletely processed insulin-like growth factor II (IGF-II) by the tumor (see also Chapter 21). The primary IGF-II translation product is pre-pro-IGF-II consisting of N-terminal signal peptide of 24 amino acids, 67 amino acid mature IGF-II, and an 89 amino acid extension (E-domain) at the C-terminus. Posttranslational processing of pre-pro-IGF-II involves removal of the N-signal sequence; O-glycosylation of one or more threonine residues of the E-domain and sequential proteolysis of the E-domain. During this process an IGF-II protein with a 21 amino extension of the E-domain (pro-IGF-IIE[68-88]) is relatively stable intermediate that may be secreted from the cell. Most of the mature IGF-II released from the liver is complexed with IGF-binding protein-3 (IGFBP3) and acid-labile subunit (ALS). This ternary protein complex is generally inactive in adults because it is unable to bind properly to tissue receptors. It is only the free IGF-II (<1%) and that bound in binary complexes (predominantly IGFBP2 and IGFBP3) that is accessible to tissue compartment and available to bind the IGF and insulin receptors. However, in patients with nonpancreatic tumors associated with hypoglycemia, incompletely processed mainly nonglycosylated forms of IGF-II are released—in particular pro-IGF-IIE (68-88) form. These incompletely processed molecules are heterogeneous in size and are also referred to as big IGF-II and have molecular mass of 10 to 17 kDa in contrast to mature IGF-II at 7.5 kDa. Pro-IGF-II can form binary complexes with IGFBPs but have reduced affinity for forming a tertiary complex with ALS. As a consequence, more of the pro-IGF-II is available for binding to the insulin receptors in the muscle to promote glucose transport and to insulin receptors in liver and kidney to reduce glucose output. The increased production of pro-IGF-II by the tumor may also displace processed IGF-II from IGFBPs, increasing free, unbound IGF-II. The IGF-II may bind to receptors for IGF-I in the pancreatic β cell to inhibit insulin secretion and in the pituitary to suppress growth hormone release. With the reduction of growth hormone, there is a consequent lowering of IGF-I levels as well as IGFBP-3 and ALS.
Size exclusion acid chromatography has been the standard method for detection of Pro-IGF-II in NICTH but the process is time consuming. Immunoblot analysis after separating the proteins on 16.5% tricine-sodium dodecyl sulphate-polyacrylamide gels is a more rapid and equally sensitive method. The IGF-II antibody used recognizes both mature and pro-IGF-II forms. In normal subjects, most of the IGF-II migrates at 7.5 kDA and a small amount in the 10 to 17 kDA region, whereas with NICTH most of the IGF-II migrates in the 10 to 17 kDa region and a small amount at 7 kDa.
The clinical syndrome of nonislet cell tumor hypoglycemia, therefore, is supported by laboratory documentation of serum insulin levels below 5 μU/mL with plasma glucose measurements of 45 mg/dL or lower. Values for growth hormone and IGF-I are also decreased. Levels of IGF-II may be increased but often are normal in quantity despite the presence of the immature, higher molecular weight form of IGF-II, which can only be detected by special laboratory techniques.
Not all the patients with NICTH have elevated pro-IGF-II. Ectopic insulin production has been described (bronchial carcinoid, ovarian carcinoma, and a small cell carcinoma of the cervix). Hypoglycemia due to IGF-I released from a metastatic large cell carcinoma of the lung has also been reported.
Treatment is aimed toward the primary tumor, with supportive therapy using frequent feedings. Diazoxide is ineffective in reversing the hypoglycemia caused by these tumors.
Alimentary (Reactive) Hypoglycemia
Some disorders cause hypoglycemia in the postprandial state. This condition occurs in patients following gastric surgery (including Roux-en-Y gastric bypass surgery), in autoimmune hypoglycemia, in islet hyperplasia (noninsulinoma pancreatogenous hypoglycemia syndrome), and occasionally in occult diabetes.
Late dumping syndrome: After major gastric surgery (gastrectomy, vagotomy, pyloroplasty, gastrojejunostomy, and laparoscopic Nissen fundoplication, Billroth II procedure, and Roux-en-Y gastric bypass), some patients develop hypoglycemia post meals especially when they consume foods containing high levels of carbohydrates. This is also referred to as the late dumping syndrome. Late dumping occurs 1 to 3 hours after a meal. Rapid delivery of a meal to the small intestine results in an initial high concentration of carbohydrates in the proximal small bowel and rapid absorption of glucose. This is countered by a hyperinsulinemic response. The high insulin levels are responsible for the subsequent hypoglycemia. The hypoglycemic symptoms include lightheadedness, sweating, confusion, and even loss of consciousness. Gastrointestinal hormones—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)—may play a role in the hyperinsulinemic response. An increased GLP-1 response has been noted in patients after total gastrectomy, esophageal resection, partial gastrectomy, and Roux-en-Y surgery. Furthermore, a positive correlation was found between the rise in plasma GLP-1 and insulin release. Decrease in requirement for gastric surgery for peptic ulcer disease and newer gastric operations such as proximal gastric vagotomy have reduced the incidence of postgastrectomy syndromes. However, as Roux-en-Y gastric bypass surgery has become a popular treatment for morbid obesity, there have been a number of reports of severe postprandial neuroglycopenia. The prevalence of the syndrome after Roux-en-Y procedure is not known. The University of Minnesota surgery group identified 14 cases of postprandial hypoglycemia in 3082 procedures (0.4%), but it is unclear how many patients may have eluded detection or failed to maintain follow-up.
Patients typically complain of the symptoms more severe after consumption of large amounts or readily absorbable carbohydrates. The mixed meal test can be used to precipitate the symptoms. The composition of the mixed meal has not been standardized, and it is reasonable to request the patient to consume a meal that leads to symptoms during everyday life. The University of Minnesota investigators formalized a high carbohydrate and a low carbohydrate test meal (Table 18–6) and showed that in patients with postgastric bypass hypoglycemia, the high carbohydrate meal resulted in hyperglycemia and concomitant hyperinsulinemia at about 30 minutes after a meal. Glucose levels then fell to a nadir (range 28-62 mg/dL) at 90 to 120 minutes. Eating the low carbohydrate meal, however, resulted in very little change in plasma glucose levels and only a modest increase in plasma insulin. The prolonged (5 hour) oral glucose tolerance test is not recommended for evaluation because a large number of healthy subjects will have a false-positive result. There have been case reports of insulinoma and noninsulinoma pancreatogenous hypoglycemia syndrome occurring in patients who present with hypoglycemia post-Roux-en-Y surgery. It is unclear how often this occurs. A careful history may identify those patients who have history of hypoglycemia with exercise or when meals are missed, and these individuals may require a formal 72-hour fast to rule out an insulinoma. Those patients with well-documented postprandial hyperinsulinemic hypoglycemia, which does not respond to medical treatment, may need to have selective calcium-stimulated angiography to identify diffuse islet cell hyperplasia (nesidioblastosis).
Table 18–6 Test Meals for Evaluation of Postprandial Hypoglycemia after Roux-en-Y Gastric Bypass Surgery. ||Download (.pdf)
Table 18–6 Test Meals for Evaluation of Postprandial Hypoglycemia after Roux-en-Y Gastric Bypass Surgery.
|High Carbohydrate Meal (79% Carbohydrate, 11% Fat, and 10% Protein; 405 kcal)||Low Carbohydrate Meal (2% Carbohydrate, 74% Fat, and 24% Protein; 415 kcal)|
|8 oz of orange juice||Decaffeinated black coffee or tea (without sugar)|
|1 slice of toast with 1 tsp of margarine and 2 tsp of jam||1 egg, a 1-oz sausage patty, and a 0.5-oz slice of cheese|
Several different treatments can be tried for the late dumping syndrome. Dietary modification is the best option but may be difficult to sustain for some patients. More frequent meals with smaller portions of less rapidly assimilated carbohydrate and more slowly absorbed fat or protein can be tried. Alpha glucosidase inhibitors (acarbose and miglitol) can be a useful adjunct to a low carbohydrate diet in some patients. Octreotide 50 μg administered subcutaneously two or three times a day 30 minutes prior to each meal has been reported to improve symptoms in patients with severe dumping refractory to other forms of medical interventions. Information regarding long-term octreotide use is however limited. Various surgical procedures to slow down gastric emptying have been reported to improve symptoms, but long-term efficacy studies are lacking. Recently it has been reported that endoscopic gastrojejunal anastomotic reduction to induce delay in gastric pouch emptying in patients with Roux-en-Y surgery improves the dumping syndrome symptoms. Partial pancreatectomy is also an option for those postgastric bypass patients with hypoglycemia who have a positive selective calcium stimulation test and in whom medical therapy has failed.
Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS): These are patients with hyperinsulinemic hypoglycemia due to generalized islet hyperplasia and nesidioblastosis. These patients predominantly have symptoms 2 to 4 hours after meals and only rarely while fasting. The majority of patients are male (70%), and all have neuroglycopenic symptoms including diplopia, dysarthria, confusion, disorientation, and even convulsions and coma. At the time of hypoglycemia, these patients have elevated insulin; C-peptide and proinsulin levels; and negative sulfonylurea, repaglinide, and nateglinide screens. Typically these patients have a negative 72-hour fast. Imaging studies are also negative. These patients have a positive selective arterial calcium stimulation test—usually positive for multiple arteries. NIPHS patients do not have mutations in the KIR6.2 and SUR1 genes, which have been abnormal in some cases of children with a syndrome of familial hyperinsulinemic hypoglycemia (see later) Gradient-guided partial or subtotal pancreatectomy relieves the hypoglycemic symptoms in the majority of patients.
Late hypoglycemia of occult diabetes: This condition is characterized by insulin release from pancreatic β cells, resulting in initial exaggeration of hyperglycemia during a glucose tolerance test. In response to this hyperglycemia, exaggerated delayed insulin release produces late hypoglycemia 4 to 5 hours after ingestion of glucose. These patients are often obese, frequently have a family history of diabetes mellitus and have impaired glucose tolerance. In the obese, treatment is directed at reduction to ideal weight. These patients also often respond to reduced intake of refined sugars with multiple, spaced, small feedings high in dietary fiber. They should be considered to have prediabetes or early diabetes (type 1 or 2) and advised to have periodic medical evaluations.
Postprandial syndrome (functional alimentary hypoglycemia): Patients present with symptoms suggestive of increased sympathetic activity—anxiety, weakness, tremor, sweating, or palpitations after meals. Physical examination and laboratory tests are normal. Previously many of these patients underwent a 5-hour oral glucose tolerance test and the detection of glucose levels in the 50s was determined to be responsible for the symptoms, and the recommendation was to modify the diet. It is now recognized that at least 10% of normal subjects who do not have any symptoms have nadir glucose levels less than 50 mg/dL during a 4- to 6-hour oral glucose tolerance test. In a study comparing responses to an oral glucose tolerance test with the response to a mixed meal test, none of the patients who had plasma glucose levels less than 50 mg/dL on oral glucose testing had low glucose values with the mixed meal. Thus, it is not recommended that these patients undergo either a prolonged oral glucose tolerance test or a mixed meal test. The patients should instead be given home blood glucose monitors (with memories) and instructed to monitor fingerstick glucose levels at the time of symptoms. Only patients who have symptoms when their fingerstick blood glucose is low (<50 mg/dL) and who have resolution of symptoms when the glucose is raised by consumption of readily absorbable carbohydrate need additional evaluation. Patients who do not have evidence for low glucose levels at the time of symptoms are generally reassured by their findings. Counseling and support should be the mainstays of therapy in this group, with dietary manipulation used only as an adjunctive form of therapy.
Disorders Associated with Low Hepatic Glucose Output
Reduced hepatic gluconeogenesis can result from a direct loss of hepatic tissue (acute yellow atrophy from fulminant viral hepatitis or toxic damage), from disorders that reduce amino acid substrate for hepatic gluconeogenesis (severe muscle wasting and inanition from anorexia nervosa, chronic starvation, uremia, and glucocorticoid deficit from adrenocortical deficiency), or from inborn errors of carbohydrate metabolism affecting glycogenolytic or gluconeogenic enzymes.
Neonatal hypoglycemia is a very common problem and can be due to a variety of causes (Table 18–7). In the first day of life, normal babies do not tolerate fasting for periods of 8 hours after delivery. Hypoglycemia in this setting is attributed to impaired ketogenesis and gluconeogenesis. This developmental immaturity in the metabolic response to fasting resolves within the first 2 to 3 days of life. Hypoglycemia in the first few days of life may be directly related to maternal factors, such as maternal diabetes, intravenous glucose use during labor and delivery, and various medications. All of these factors induce a transient hyperinsulinism in the newborn. Prolonged neonatal hypoglycemia may result from perinatal stress, the Beckwith-Wiedeman syndrome, and hypopituitarism. The risk for hypoglycemia can persist for weeks to months. Persistent hypoglycemia may result from: (1) a deficiency in one or more counterregulatory hormones; (2) defects in glycogenolysis, gluconeogenesis, or fatty acid oxidation; or (3) congenital hyperinsulinism, the various forms of which are discussed further below.
Table 18–7 Types of Congenital Hyperinsulinism and Their Causes. ||Download (.pdf)
Table 18–7 Types of Congenital Hyperinsulinism and Their Causes.
|Infants of diabetic mothers|
|Small for gestational age, asphyxia, and stress in infants|
|Syndromes (eg, Beckwith-Wiedemann, Soto)|
|Defects in ATP-dependent potassium channel|
|Sulfonylurea receptor (SUR)|
|Focal vs diffuse disease|
|Short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD)|
As with adults, hyperinsulinism is the most frequent cause of persistent hypoglycemia in infants and children. As compared to adults, where the most common cause of hyperinsulinism is an insulin-secreting adenoma, in infants hyperinsulinism most likely stems from an underlying genetic disorder. This condition has been referenced in various ways, including persistent hyperinsulinemic hypoglycemia of infancy or islet dysregulation syndrome, but hereafter will be referred to as congenital hyperinsulinism. Transient congenital hyperinsulinism is a common disorder in the immediate neonatal period. Persistent disorders are rarer, occurring in approximately 1 in 50,000. This problem was originally attributed to an anomaly in islet development, termed nesidioblastosis, a reference to endocrine cell budding from pancreatic ducts. However, this budding has since been noted to represent a normal developmental process during the first year of life. Recent advances in our understanding of the regulation of insulin secretion have begun to elucidate the underlying pathophysiology of this complex disease. Congenital hyperinsulinism has now been attributed to at least seven different gene defects. However, depending on the series cited, no genetic explanation is found in 50% or more of cases. Timely diagnosis and aggressive treatment are essential to prevent long-term neurologic sequelae in the affected individual.
Infants of Diabetic Mothers
The fetuses of mothers with poorly regulated diabetes are exposed to sustained hyperglycemia, leading to increased fetal insulin secretion, with resultant macrosomia. This increased insulin secretion persists postpartum and usually resolves after several days. As a result, infants of diabetic mothers are at high risk of developing hypoglycemia after birth. They can usually be managed with early, frequent feedings or intravenous glucose until insulin secretion has normalized, often 1 to 2 days after birth.
Small for Gestational Age, Asphyxiation, and Other Conditions in Newborns
Various perinatal stresses are known to induce hyperinsulinism. Small-for-gestational age and asphyxiated newborns, usually from toxemic mothers, frequently experience hyperinsulinism and hypoglycemia. Hyperinsulinism is also reported in erythroblastosis fetalis, sepsis, cerebral hemorrhage, and severely stressed newborns. Hypoglycemia usually resolves within a period of several days or weeks but may persist in these settings for 6 to 12 months. Some newborns with Beckwith-Wiedemann syndrome and Soto syndrome (also known as cerebral gigantism) show β cell hyperplasia and experience transient hypoglycemia from hyperinsulinism.
Persistent hyperinsulinism, continuing for more than several weeks, results from a group of heterogeneous disorders, rather than a single entity, and the various subtypes are discussed below. These forms may be classified in a variety of different ways, including usual time of presentation (shortly after birth vs after months to years of life); mode of genetic transmission (autosomal recessive vs dominant); or anatomic (focal vs diffuse). In this section, the forms are grouped into defects in the pancreatic β cell ATP-sensitive potassium channel, defects affecting intracellular metabolism, and several other miscellaneous conditions.
Sulfonylurea receptor and Kir6.2—The most common cause of congenital hyperinsulinism appears to be related to defects in the pancreatic β cell ATP-sensitive potassium channel. This channel consists of a multimer of two proteins, the sulfonylurea receptor (SUR), a member of the ATP-binding cassette superfamily, and Kir6.2, a member of a family of inwardly rectifying potassium channels. With increases in intracellular ATP, the channel closes, leading to depolarization and insulin secretion (see Chapter 17). Defects in either component of the channel result in channel closure, inappropriate β cell depolarization, and secretion of insulin, even in the face of low or normal glucose concentrations.
The two genes encoding the channel components are located in tandem on chromosome 11p15. Numerous mutations have now been described and appear to occur more frequently in the SUR than the Kir6.2 gene. They are usually autosomal recessive defects, but dominant defects have also been reported. Sequencing of these molecules is now available commercially and may not be merely of academic interest: patients harboring SUR or Kir6.2 mutations often do not respond well to medical therapy. Thus, knowledge of the underlying defect may influence treatment decisions for a particular patient as well as inform the family about risk to future children. Relative to other forms of congenital hyperinsulinism, patients with defects in the ATP-sensitive potassium channel often present early in life, with more marked clinical symptomatology, including macrosomia. They experience early onset and severe hypoglycemia that requires high rates of glucose infusion to normalize serum glucose concentrations and typically require pancreatectomy to restore euglycemia.
Focal versus diffuse disease—Two histologically distinct forms of congenital hyperinsulinism have been described, a diffuse form, mentioned above, which constitutes 35% to 70% of cases, depending on the series cited, and a focal form (focal adenomatous hyperplasia). Diagnosis of the focal form is made by pancreatic venous sampling and by perioperative extemporaneous histologic examination. [18F]Fluorodopa positron emission tomography may also be of utility in defining focal lesions. Histologic examination of the focal form reveals focal hyperplasia, with hypertrophied β cells harboring giant nuclei, in contrast to the diffuse form, where all the islets of Langerhans are irregular in size and contain hypertrophied β cells. The molecular explanation for the focal defect is based on a two-hit model, in which the child already harbors a mutant allele from a paternally derived potassium-ATP channel defect. Subsequent somatic loss of heterozygosity for the maternal 11p chromosome is associated with focal disease and may result from a decrease in dosage of an independent growth-suppressing gene(s) in this region. The distinction between these two forms of hyperinsulinism has potentially important implications for therapy, because patients with focal disease may be cured with more limited partial pancreatectomy, whereas those with the diffuse form require more aggressive near-total resection. Such patients can only be fully evaluated and treated at centers equipped with a team of endocrinologists, interventional radiologists, pathologists, and surgeons with expertise in this disorder.
The second most common form of congenital hyperinsulinism is the hyperinsulinism-hyperammonemia syndrome, which results from activating mutations of the glutamate dehydrogenase (GDH) gene. This condition is inherited in autosomal dominant fashion. This enzyme mediates oxidative deamination of glutamate to alpha ketoglutarate. Activating mutations impair GDH sensitivity to guanosine triphosphate, an allosteric inhibitor, and increase sensitivity to leucine, an allosteric activator. With increased GDH activity, increased production of alpha ketoglutarate with subsequent oxidation in the Krebs cycle generates increased ATP, which in turn activates the ATP-sensitive potassium channel and leads to depolarization and insulin secretion. GDH is also expressed in hepatocytes, and increased activity generates ammonia via glutamate oxidation. Thus, one hallmark of this defect is increased ammonia concentrations three to five times normal. The patients with GDH mutations usually have a milder course than those with defects in the ATP-sensitive potassium channel, often presenting outside of the neonatal period. They often have postprandial hypoglycemia, particularly in response to higher protein loads, but may also manifest fasting hypoglycemia. They usually respond well to diazoxide, and many are able to eventually discontinue treatment.
A much rarer form of autosomal dominant hyperinsulinism results from mutations in glucokinase, the first and rate-limiting step in glycolysis, and an enzyme that is considered to play an essential role in glucose sensing by the β cell. Individuals heterozygous for inactivating mutations have a form of maturity onset diabetes of the young. On the other hand, activating mutations have been described in two families that result in increased rates of glycolysis at lower glucose concentrations. The resultant increase in the intracellular ATP/ADP ratio increases insulin secretion at any given serum glucose concentration, resulting in hypoglycemia.
An entity referred to as exercise-induced hyperinsulinism has been described, in which hyperinsulinism is noted following exercise. An underlying genetic cause has not yet been proven, although it is suspected that this represents another metabolic defect. This problem appears to be milder than the others described earlier, and it neither presents in the neonatal period nor results in fasting hypoglycemia. A recent report suggested an autosomal dominant pattern of inheritance in multiple members of two families. Hyperinsulinism was induced by exercise and by pyruvate infusion, suggesting that this disorder results from abnormal transport or metabolism of pyruvate in β cells.
Another autosomal recessive form of congenital hyperinsulinism results from mutations in the gene encoding the short chain L-3-hydroxyacyl-CoA dehydrogenase. This enzyme mediates the penultimate step in fatty acid beta oxidation and as such represents the first link between defects in fatty acid metabolism and insulin secretion. However, it is not yet clear how this defect results in congenital hyperinsulinism.
Congenital disorders in glycosylation have also been linked with congenital hyperinsulinism. The mechanism is unclear, although hypoglycosylation of the SUR with a resultant defect in trafficking to the cell membrane has been offered as a possible explanation. Nonetheless, these patients appear to be responsive to diazoxide, suggesting that at least some functional ATP-sensitive potassium channels reach the cell surface. Affected individuals have multisystem disorders, including neurologic defects.
Despite the evolving elucidation of defects known to be associated with congenital hyperinsulinism, the underlying diagnosis remains unknown in up to one-half of infants diagnosed with this condition.
The cardinal symptoms of hyperinsulinism are recurrent episodes of hypoglycemia and can occur any time after birth until several years of age, or manifest even later in life, depending on the nature and severity of the defect. As in adults, the symptoms of hypoglycemia are secondary to adrenergic responses or neuroglycopenia. However, in neonates and infants, symptoms are difficult to detect and may be less specific. They may include tremors, cyanosis, hypothermia, apnea or irregular breathing, lethargy, apathy, limpness, refusal to eat, high-pitched cries, and seizures of any type. Even if newborns appear asymptomatic, hypoglycemia can be as severe as in symptomatic neonates.
The differential diagnosis for hypoglycemia in a neonate is quite long and includes deficiencies in counterregulatory hormones (eg, growth hormone, ACTH, glucocorticoids); defects in gluconeogenesis, glycogen synthesis, and breakdown; and disorders in fatty acid metabolism. Hyperinsulinism is suspected in hypoglycemic newborns or infants who require unusually high glucose infusion rates (12-30 mg/kg/min) to maintain blood glucose levels in the target range. Macrosomia may be another clue to hyperinsulinism, although it is not always present. The crucial diagnostic step is to obtain a critical blood sample for glucose, insulin, growth hormone, cortisol, blood gas, lactate, free fatty acids, and ketones (β-hydroxybutyrate) during hypoglycemia. Urinary ketones should be measured in the first urine after hypoglycemia. Insulin levels must often be measured during several episodes of hypoglycemia because insulin levels at times of hypoglycemia are not always diagnostically elevated. In fact, insulin levels that are inappropriately measurable during episodes of hypoglycemia are still consistent with the diagnosis. As in adults, the hallmarks of hyperinsulinism include measurable plasma insulin in the face of hypoglycemia (glucose <40 mg/dL), low or unmeasurable ketones and free fatty acids, and hyperresponsiveness to glucagon challenge, with the glycemic response to 0.5 to 1 mg of parenteral glucagon of more than 30 mg/dL (with glucose monitored every 15 minutes for up to 45 minutes after glucagon injection). Low IGF-binding protein (IGFBP) 1 levels also suggests this diagnosis, as insulin suppresses IGFBP1 secretion from the liver.
Management of children with congenital hyperinsulinism remains one of the most challenging problems for pediatric endocrinologists, and affected children should be transferred to a tertiary center that has experience in managing such children. Patients may require high glucose infusion rates to maintain euglycemia, and thus a secure central line is usually necessary. They also require frequent glucose monitoring, extensive ongoing laboratory assessment to establish the underlying diagnosis, and a series of medical and/or surgical interventions to effect a cure.
Hypoglycemia in infancy has to be treated aggressively in order to prevent long-term neurologic sequelae. Relative to adults, younger children (up to age 5 to 6 years) appear to be particularly vulnerable to such damage. Those with hyperinsulinism are particularly at risk, because ketone bodies are not present as an alternative fuel source. The therapeutic goal is to achieve glucose levels above 60 mg/dL while the infant is on an appropriate feeding schedule for age. Infants receiving appropriate therapy must be able to support a fast for at least 4 to 6 hours without hypoglycemia. In selected cases in which food refusal or intercurrent illness is a problem, hypoglycemia can be prevented by placing a gastrostomy tube to administer food on a regular basis.
For acute management of hypoglycemia, stabilization of blood glucoses may require infusion rates of glucose up to 20 to 30 mg/kg/min, well above the 4 to 8 mg/kg/min needed to stabilize most neonates. Some centers employ aggressive enteral feeding, using frequent feeds or continuous feeding via nasogastric or gastrostomy tube, with or without cornstarch, as a means to avoid hypoglycemia. The following drugs are also used in the medical management of hyperinsulinemic hypoglycemia.
Diazoxide—Diazoxide is the drug of choice in neonates who cannot be weaned from intravenous glucose. Diazoxide increases blood glucose by stabilizing the ATP-sensitive potassium channel in the open state, thereby inhibiting membrane depolarization and insulin secretion. Functionally intact SUR and Kir6.2 proteins are necessary for the full action of the drug, and thus, patients with channel defects often do not respond, whereas those with other forms of hyperinsulinism do exhibit salutary responses. Diazoxide also increases catecholamine release, which suppresses insulin release and inhibits insulin's actions peripherally. The initial recommended dose is 10 to 15 mg/kg/d divided every 8 hours, up to a maximal dose of 20 mg/kg/d. Positive responses are usually seen within 48 hours if they are going to occur. Diazoxide has several important side effects that should be considered. Fluid retention can be managed by simultaneous administration of chlorothiazide. Hypertrichosis and coarse facial changes may become quite striking and can be reduced only by decreasing the dose or discontinuing the diazoxide altogether. Hyperuricemia, leukopenia, and thrombocytopenia are rare, but routine serum studies must be monitored while therapy continues. Diazoxide is also an antihypertensive drug, but these effects are rarely encountered with oral administration.
Depending on the study cited, diazoxide appears to be efficacious in only one-fourth to one-half of the patients with hyperinsulinism and appears to be less likely to work in those patients presenting in the immediate newborn period, a population that often has more marked defects in ATP-sensitive potassium channel activity. Thus, in those patients with persistent hyperinsulinism, determining whether mutations are present in SUR or Kir6.2 genes may help anticipate the response to medical therapy and predict the need for more definitive surgical intervention.
Somatostatin analogs—This is usually a second-line approach, for those unresponsive to diazoxide. Somatostatin acts via a G protein–coupled receptor to lower intracellular calcium and to hyperpolarize the β cell membrane, thereby inhibiting insulin release. Somatostatin has a half-life of only 1 to 3 minutes, but the synthetic analog octreotide may be administered at intervals of up to 8 hours or via continuous subcutaneous infusion and is efficacious in some patients with congenital hyperinsulinism. A starting dose of 5 to 10 μg/kg/d, administered either as an intermittent bolus or via continuous subcutaneous infusion in a pump, often produces salutary initial responses, but because of tachyphylaxis, the dose sometimes has to be increased to as much as 40 μg/kg/d. Some physicians advocate octreotide in patients who fail to respond to diazoxide therapy alone. However, optimal control of blood glucose often cannot be achieved by adding octreotide, and partial pancreatectomy is necessary. Nonetheless, the medication may help stabilize blood glucose concentrations in the preoperative period and may prove efficacious postoperatively in those patients who have persistent hyperinsulinism even with reduced β cell mass. There are some reports of long-term success (>5 years) with octreotide alone.
Short-term side effects are mostly self-limited within the first several weeks of therapy. Octreotide has nonspecific effects on the gastrointestinal tract, including decreased perfusion of the splanchnic circulation, gallbladder contractility, and bile secretion. Short-term effects may include vomiting, abdominal distension, and steatorrhea, with later risk of cholelithiasis. Possible inhibitory effects of octreotide on other hormonal axes, including effects on the pituitary somatotrope, adrenal, and thyroid, raise concerns about its long-term use, although some centers report successful and uneventful use for years without significant problems.
Glucagon—Glucagon has a place in the management of hyperinsulinism during initial stabilization of the hypoglycemic infant in the intensive care unit or prior to surgery. This agent stimulates hepatic glycogenolysis and is very effective in these patients because their glycogen stores are replete. A variety of doses has been shown to be effective, including a bolus of 0.2 mg intravenously in cases of severe hypoglycemia followed by a continuous infusion at a dose of 2 to 10 mg/kg/h. An intramuscular glucagon injection may also be used as an emergency treatment of recurrent hypoglycemic episodes at home. Attempts have been made to administer glucagon continuously via subcutaneous infusion with limited success.
Calcium antagonists—Because calcium influx is required for insulin secretion, calcium antagonists could play a potential role in the treatment of hyperinsulinism. Calcium channel blockers also decrease the transcriptional response of insulin to glucose. However, only rare and limited success has been achieved with this class of drugs, perhaps because of failure to block calcium channels selectively within the β cells.
Partial pancreatectomy is undertaken when maintenance of euglycemia cannot be achieved with medical treatment alone. The initial surgical procedure of choice has traditionally been a 95% pancreatectomy. However, such procedures are now being reconsidered, with the appreciation that some of these infants may have a focal rather than diffuse process and may require only selective resection of the affected pancreatic tissue in order to effect a cure. Unfortunately, only a limited number of medical centers around the world are now equipped to conduct the pre- and perioperative evaluation to distinguish focal from diffuse disease, which includes selective venous sampling and histological analysis.
Even with more aggressive resections, β cell mass reduction does not always lead to euglycemia, and medical therapy may have to be continued following surgery. If this fails to restore euglycemia, a second surgical intervention may be required in which near-total pancreatectomy (99%) is performed. Potential surgical complications include intraoperative injury to the common bile duct and adhesions with intestinal obstruction. Additional complications include exocrine pancreatic insufficiency, often requiring oral supplements at mealtimes, and diabetes mellitus.
Neurologic sequelae are the major concern with severe hypoglycemia during infancy and childhood. Multiple episodes of hypoglycemia are more often associated with sequelae than one severe hypoglycemic episode with convulsions. At least one-third of patients with congenital hyperinsulinism suffer from developmental delay based on follow-up via a telephone survey.
Patients with the familial form of congenital hyperinsulinism who harbor mutations in the SUR receptor may be at additional neurologic risk. The SUR is expressed in the brain, and defects in this molecule could potentially interfere with neural development. The role of this receptor in the brain, however, has yet to be elucidated.
Affected individuals also appear to be at higher risk for later development of diabetes. This problem may be related to reduced β cell mass following pancreatectomy or from β cell apoptosis following chronic depolarization in subjects who harbor channel defects.