The Hypoglycemic States:
Current Medical Diagnosis and Treatment 2008
INTRODUCTION
Spontaneous hypoglycemia in adults is of two principal types: fasting and postprandial. Symptoms begin at plasma glucose levels in the range of 60 mg/dL and impairment of brain function at approximately 50 mg/dL. Fasting hypoglycemia is often subacute or chronic and usually presents with neuroglycopenia as its principal manifestation; postprandial hypoglycemia is relatively acute and is often heralded by symptoms of neurogenic autonomic discharge (sweating, palpitations, anxiety, tremulousness).
(Table 1.) Fasting hypoglycemia may occur in certain endocrine disorders, such as hypopituitarism, Addison's disease, or myxedema; in disorders related to liver malfunction, such as acute alcoholism or liver failure; and in instances of renal failure, particularly in patients requiring dialysis. These conditions are usually obvious, with hypoglycemia being only a secondary feature. When fasting hypoglycemia is a primary manifestation developing in adults without apparent endocrine disorders or inborn metabolic diseases from childhood, the principal diagnostic possibilities include (1) hyperinsulinism, due to either pancreatic B cell tumors or islet hyperplasia surreptitious administration of insulin (or sulfonylureas), and (2) hypoglycemia due to non–insulin-producing extrapancreatic tumors.
Postprandial (reactive) hypoglycemia may be classified as early (within 2–3 hours after a meal) or late (3–5 hours after eating). Early, or alimentary, hypoglycemia occurs when there is a rapid discharge of ingested carbohydrate into the small bowel followed by rapid glucose absorption and hyperinsulinism. It may be seen after gastrointestinal surgery and is particularly associated with the dumping syndrome after gastrectomy. In some cases, it is functional and may represent overactivity of the parasympathetic nervous system mediated via the vagus nerve. Rarely, it results from defective counterregulatory responses such as deficiencies of growth hormone, glucagon, cortisol, or autonomic responses.
Alcohol-related hypoglycemia is due to hepatic glycogen depletion combined with alcohol-mediated inhibition of gluconeogenesis. It is most common in malnourished alcohol abusers but can occur in anyone who is unable to ingest food after an acute alcoholic episode followed by gastritis and vomiting.
Immunopathologic hypoglycemia is an extremely rare condition in which anti-insulin antibodies or antibodies to insulin receptors develop spontaneously. In the former case, the mechanism appears to relate to increasing dissociation of insulin from circulating pools of bound insulin. When antibodies to insulin receptors are found, most patients do not have hypoglycemia but rather severe insulin-resistant diabetes and acanthosis nigricans. However, during the course of the disease in these patients, certain anti-insulin receptor antibodies with agonist activity mimicking insulin action may develop, producing severe hypoglycemia.
Factitious hypoglycemia is self-induced hypoglycemia due to surreptitious administration of insulin or sulfonylureas.Hypoglycemia Due to Pancreatic B Cell Tumors
- Hypoglycemic symptoms—frequently neuroglycopenic (confusion, blurred vision, diplopia, anxiety, convulsions).
- Immediate recovery upon administration of glucose.
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Fasting hypoglycemia in an otherwise healthy, well-nourished adult is rare, and is most commonly due to an adenoma of the islets of Langerhans. Ninety percent of such tumors are single and benign, but multiple adenomas can occur as well as malignant tumors with functional metastases. Adenomas may be familial, and multiple adenomas have been found in conjunction with tumors of the parathyroids and pituitary (multiple endocrine neoplasia type 1 [MEN 1]).
The most important prerequisite to diagnosing an insulinoma is simply to consider it, particularly in relatively healthy-appearing persons who have fasting hypoglycemia associated with some degree of central nervous system dysfunction such as confusion or abnormal behavior. A delay in diagnosis can result in unnecessary treatment for psychomotor epilepsy or psychiatric disorders and may cause irreversible brain damage. In longstanding cases, obesity can result as a consequence of overeating to relieve symptoms.
Whipple's triad is characteristic of hypoglycemia regardless of the cause. It consists of (1) a history of hypoglycemic symptoms, (2) an associated fasting blood glucose of 40 mg/dL or less, and (3) immediate recovery upon administration of glucose. The hypoglycemic symptoms in insulinoma often develop in the early morning or after missing a meal. Occasionally, they occur after exercise. They typically begin with evidence of central nervous system glucose lack and can include blurred vision or diplopia, headache, feelings of detachment, slurred speech, and weakness. Personality and mental changes vary from anxiety to psychotic behavior, and neurologic deterioration can result in convulsions or coma. Sweating and palpitations may not occur.
Hypoglycemic unawareness is very common in patients with insulinoma. They adapt to chronic hypoglycemia by increasing their efficiency in transporting glucose across the blood-brain barrier, which masks awareness that their blood glucose is approaching critically low levels. Counterregulatory hormonal responses as well as neurogenic symptoms such as tremor, sweating, and palpitations are therefore blunted during hypoglycemia. If lack of these warning symptoms prevents recognition of the need to eat to correct the problem, patients can lapse into severe hypoglycemic coma. However, symptoms and normal hormone responses during experimental insulin-induced hypoglycemia have been shown to be restored after successful surgical removal of the insulinoma. Presumably with return of euglycemia, adaptive effects on glucose transport into the brain are corrected, and thresholds of counterregulatory responses and neurogenic autonomic symptoms are therefore restored to normal.
B cell adenomas do not reduce secretion in the presence of hypoglycemia, and the critical diagnostic test is to demonstrate inappropriately elevated serum insulin levels at a time when hypoglycemia is present. A reliable serum insulin level (radioimmunoassay) of 6 microunit/mL or more in the presence of blood glucose values below 40 mg/dL is diagnostic of inappropriate hyperinsulinism. Immunochemiluminometric assays (ICMA) have sensitivities of less than 1 microunit/mL, and with these assays, the cutoffs for insulinomas is insulin level 3 microunit/mL or higher. Other causes of hyperinsulinemic hypoglycemia must be considered, including factitious administration of insulin or sulfonylureas. Factitious use of insulin will result in suppression of endogenous insulin secretion and a low C-peptide levels. An elevated circulating proinsulin level in the presence of fasting hypoglycemia is characteristic of most B cell adenomas 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.
In patients with epigastric distress, a history of renal stones, or menstrual or erectile dysfunction, a serum calcium, gastrin, or prolactin level may be useful in screening for MEN 1 associated with insulinoma.
Prolonged fasting under hospital supervision until hypoglycemia is documented is probably the most dependable means of establishing the diagnosis, especially in men. In 30% of patients with insulinoma, the blood glucose levels often drop below 40 mg/dL after an overnight fast, but some patients require up to 72 hours to develop symptomatic hypoglycemia. However, the term "72-hour fast" is actually a misnomer in most cases since the fast should be immediately terminated as soon as symptoms appear and laboratory confirmation of hypoglycemia is available. In normal male subjects, the blood glucose does not fall below 55–60 mg/dL during a 3-day fast. In contrast, in normal premenopausal women who have fasted for only 24 hours, the plasma glucose may fall normally to such an extent that it can reach values as low as 35 mg/dL. In these cases, however, the women are not symptomatic, presumably owing to the development of sufficient ketonemia to supply energy needs to the brain. Insulinoma patients, on the other hand, become symptomatic when plasma glucose drops to subnormal levels, since inappropriate insulin secretion restricts ketone formation. Moreover, the demonstration of a nonsuppressed insulin level >6 microunit/mL using a RIA assay (> 3 microunit/mL using an ICMA assay) in the presence of hypoglycemia suggests the diagnosis of insulinoma. If hypoglycemia does not develop in a male patient after fasting for up to 72 hours—and particularly when this prolonged fast is terminated with a period of moderate exercise—insulinoma must be considered an unlikely diagnosis. A suggested protocol for the supervised fast is shown in Table 2.
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-hydroxybutyrate and sulfonylurea measurements. Then give oral fast-acting carbohydrate followed by a meal. If the patient is confused or unable to take oral agents, then administer 50 mL of 50% dextrose intravenously over 3 to 5 minutes. Do not conclude a fast based simply on a capillary blood glucose measurement—wait for the laboratory glucose value—unless the patient is very symptomatic and it would be dangerous to wait.Stimulation tests
Stimulation with pancreatic B cell secretagogues such as tolbutamide, glucagon, or leucine is generally not needed in most cases if basal insulin is found to be nonsuppressible and therefore inappropriately elevated during fasting hypoglycemia.
Intravenous glucagon (1 mg over 1 minute) can be useful in patients with "borderline" fasting inappropriate hyperinsulinism. A serum insulin rise above baseline of 200 microunit/mL or more at 5 and 10 minutes strongly suggests insulinoma, although poorly differentiated tumors may not respond. Glucagon has the advantage over tolbutamide of correcting rather than provoking hypoglycemia during stimulation testing and is diagnostic in 60–70% of patients with insulinoma. False-negative results can occur if the tumor is poorly differentiated and agranular.
Preoperative Localization of B Cell Tumors
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 to the pancreas since that is where virtually all insulinomas originate.
A spiral CT angiography of the pancreas should be performed to rule out a large tumor of the pancreas or hepatic metastases from a malignant islet cell tumor. Endoscopic ultrasonographic examination of the pancreas can also be helpful in identifying the pancreatic lesions. Because of the small size of these tumors (averaging 1.5 cm in diameter in one large series), imaging studies do not necessarily identify all the tumors. Patients who do not have an obvious tumor on imaging (but have a definite biochemical diagnosis) should undergo selective calcium-stimulated angiography. 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. Calcium stimulates insulin release from insulinomas but not normal islets, and so a step-up of insulin levels regionalizes the hyperinsulinism to the head of the pancreas for the gastroduodenal artery, to the uncinate process for the superior mesenteric artery, and to the body and tail of the pancreas for the splenic artery. This technique may also provide data that are particularly helpful when multiple insulinomas are suspected (MEN 1) and it has become a major tool in confirming the diagnosis of diffuse islet hyperplasia in the recently described noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) (see below). Since diazoxide might interfere with this test, it should be discontinued for at least 48–72 hours before sampling. An infusion of dextrose may be required, therefore, and 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 identifies up to 98% of tumors.
It is imperative that the surgeon be convinced that the diagnosis of insulinoma has been unequivocally made by clinical and laboratory findings. Only then should surgery be considered, as there is no justification for exploratory operation—just as there is none for the use of current localization techniques as a preoperative diagnostic tool. Resection by a surgeon with previous experience in removing pancreatic B cell tumors is the treatment of choice. In patients with a single benign adenoma 90–95% have a successful cure at the first surgical attempt when intraoperative ultrasound is used by a skilled surgeon. Blood glucose should be monitored throughout surgery, and 10%dextrose in water should be infused at a rate of 100 mL/h or faster. In cases where the diagnosis has been established but no adenoma is located after careful palpation and 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 schedule a selective arterial calcium stimulation with hepatic venous sampling to locate the tumor site prior to a repeat operation. Laparoscopy using ultrasound and enucleation has been successful with a single tumor of the body or tail of the pancreas, but open surgery remains necessary for tumors in the head of the pancreas.
In patients with inoperable functioning islet cell carcinoma and in approximately 5–10% of MEN 1 cases when subtotal removal of the pancreas has failed to produce cure, reliance on frequent feedings is necessary. Since most tumors are not responsive to glucose, carbohydrate feedings every 2–3 hours are usually effective in preventing hypoglycemia, although obesity may become a problem. Diazoxide, 300–600 mg (or 3 mg to 8 mg/kg; 50 mg/mL oral suspension) daily orally in two or three divided doses, is the treatment of choice. Hydrochlorothiazide, 25–50 mg daily, should also be prescribed to counteract the sodium retention and edema secondary to diazoxide therapy as well as to potentiate its hyperglycemic effect. If patients are unable to tolerate diazoxide because of gastrointestinal upset, hirsutism, or edema, the calcium channel blocker verapamil may be beneficial in view of its inhibitory effect on insulin release from insulinoma cells. Octreotide, a potent long-acting synthetic octapeptide analog of somatostatin, has been used to inhibit release of hormones from a number of endocrine tumors. A dose of 50 mcg of octreotide injected subcutaneously twice daily has been tried in cases where surgery failed to remove the source of hyperinsulinism. However, its effectiveness is limited since its affinity for somatostatin receptors of the pancreatic B cell is very much less than for those of the anterior pituitary somatotrophs for which it was originally designed as treatment for acromegaly. When hypoglycemia persists after attempted surgical removal of the insulinoma and if diazoxide or verapamil is poorly tolerated or ineffective, multiple small feedings may be the only recourse until more selective somatostatin receptor agonists are available. Streptozocin can decrease insulin secretion in islet cell carcinomas, and effective doses have been delivered via selective arterial catheter so that the undue renal toxicity that characterized early experience is less of a problem.
When insulinoma is diagnosed early and cured surgically, complete recovery is likely, although brain damage following prolonged severe hypoglycemia is not reversible. A significant increase in survival rate has been shown in streptozocin-treated patients with islet cell carcinoma, with reduction in tumor mass as well as decreased hyperinsulinism