Hypoglycemia has conventionally been classified into two categories: fasting (or postabsorptive) hypoglycemia and reactive (or postprandial) hypoglycemia. However, with very rare exceptions, all patients with clinically important hypoglycemia have a disorder that causes fasting hypoglycemia. In some cases hypoglycemia also develops in these patients shortly after meals, but the differential diagnosis remains that of fasting hypoglycemia.
Although once widely used for the diagnosis of reactive hypoglycemia, the oral glucose tolerance test is unreliable and should not be used to diagnose suspected hypoglycemia. Patients given the diagnosis of reactive hypoglycemia based on this test rarely have hypoglycemia during daily life (after ordinary meals or during spontaneous symptoms).
The major causes of fasting hypoglycemia are outlined in
Box 304-1. Hypoglycemia occurs when glucose use exceeds glucose production. Fasting hypoglycemia in patients with the various forms of hyperinsulinism and in those with tumors secreting insulin-like hormones is due to suppressed hepatic glucose production coupled with inappropriately high rates of glucose utilization. Impaired hepatic glucose production with ongoing obligate glucose utilization (e.g., by the brain) is believed to be the predominant mechanism of fasting hypoglycemia attributable to drugs, hormonal deficits, hepatic dysfunction, chronic renal failure, and the childhood hypoglycemic disorders. Clearly, accelerated glucose utilization in conditions such as vigorous exercise and pregnancy could exacerbate fasting hypoglycemia attributable to any of the disorders listed. However, accelerated glucose utilization alone seldom results in fasting hypoglycemia because of the normal capacity to increase glucose production.
By far the most common cause of hypoglycemia is therapy of diabetes mellitus with insulin or sulfonylureas. Although hypoglycemia is a major therapeutic limitation in diabetes, it seldom presents a diagnostic problem. These drugs may also be used to produce factitious hypoglycemia, however, especially among medical personnel and others with knowledge of diabetes. Ethanol inhibits gluconeogenesis but not glycogenolysis. Thus it causes hypoglycemia only when hepatic glycogen is depleted in fasting or malnourished individuals. Salicylates cause hypoglycemia in children by an unknown mechanism. Pentamidine and quinine stimulate insulin release and presumably cause hypoglycemia by this means. A number of other drugs have been associated with hypoglycemia, but in most cases other potential causes of hypoglycemia were present and a clear causal relationship was not established.
Renal insufficiency is a major factor associated with hypoglycemia in hospitalized patients. The mechanisms are not known, although the majority of patients who develop hypoglycemia are malnourished. The development of renal failure in diabetes mellitus often reduces insulin requirements and increases the risk of hypoglycemia. Hepatic disease can cause hypoglycemia as a result of inadequate glucose production. Because the liver is normally able to increase glucose output several-fold, only severe hepatic dysfunction causes hypoglycemia. Hypoglycemia in patients with cardiac failure or sepsis is probably a result of impaired hepatic and renal function. Hypoglycemia has rarely been attributed to malnutrition without other disorders.
Adrenocortical insufficiency commonly leads to anorexia and weight loss. Further, cortisol is required to maintain normal levels of hepatic gluconeogenic enzymes and to mobilize gluconeogenic precursors; it also antagonizes the effects of insulin. Deficiency of growth hormone produces enhanced insulin sensitivity. Despite these effects, in most adults with cortisol or growth hormone deficiency, or both, hypoglycemia does not develop. On the other hand, hypoglycemia is an important manifestation of these disorders in children. Combined deficiency of glucagon and epinephrine occurs in some patients with insulin-dependent diabetes mellitus and greatly increases the risk of insulin-induced hypoglycemia. Deficiency of either glucagon or epinephrine alone, however, would not be expected to produce hypoglycemia; indeed, hypoglycemia that is due to deficiency of either or both has not been shown convincingly in nondiabetic patients.
Fasting hypoglycemia occurs in some patients with large extrapancreatic tumors, especially mesenchymal tumors such as mesotheliomas and retroperitoneal sarcomas, and hepatic and adrenal carcinomas. In many cases hypoglycemia is caused by a combination of tu-mor production of a precursor of insulin-like growth factor II (IGF-II) and increased access of IGF-II to target tissues attributable to a decrease in plasma IGF-binding proteins that normally sequester IGF-II within the circulation. Suppression of glucagon and growth hormone secretion by IGF-II may also contribute to hypoglycemia. Ectopic production of insulin by extrapancreatic tumors has not been described convincingly.
The common denominator of pancreatic beta-cell disorders that produce endogenous hyperinsulinism is the failure to suppress insulin secretion normally when the plasma glucose concentration declines in the fasting state. This failure results in relative hyperinsulinemia during hypoglycemia (i.e., a plasma insulin concentration that is inappropriately high relative to the ambient plasma glucose concentration). The concept of relative hyperinsulinemia is central to the diagnosis of fasting hypoglycemia attributable to hyperinsulinism.
Endogenous hyperinsulinism in adults is almost always due to pancreatic beta-cell tumors or insulinomas, which can occur anywhere in the pancreas. In about 80% of cases there is a single benign adenoma, whereas about 10% of cases are due to multiple benign adenomas and 5% to 10% are due to carcinomas. Insulinomas occur in all age-groups, although two thirds are diagnosed between the ages of 30 and 60 years. Approximately 60% of reported cases have been in women. Islet cell tumors, often multiple and including beta-cell tumors, are one component of the multiple endocrine neoplasia type I syndrome, along with hyperparathyroidism and pituitary tumors. This familial disorder is inherited as an autosomal dominant trait.
Most infants with persistent hyperinsulinism do not have insulinomas or other detectable pathologic lesions. A genetic defect of the sulfonylurea receptor of beta cells appears to cause excessive insulin secretion in these patients. Nesidioblastosis (islet cells interspersed among pancreatic exocrine cells), once believed to be the basis for hyperinsulinism, is a normal finding in infants and is not associated with hypoglycemia.
Intermittent hypoglycemia with inappropriately high serum free insulin concentrations has been recognized in a few patients found to have serum autoantibodies to insulin. It is presumed that insulin periodically dissociates from these antibodies, causing hyperinsulinism and hypoglycemia. Most of these patients have other evidence of autoimmune disease. Autoantibodies to the insulin receptor usually produce insulin resistance, but in rare patients they may cause hypoglycemia, presumably by mimicking the effects of insulin.
A number of hypoglycemic disorders are unique to or typically present in infancy or childhood. Transient neonatal hypoglycemia in infants of diabetic mothers is thought to be due to chronic fetal hyperglycemia with resultant fetal hypersecretion of insulin that persists for a time after birth. Many neonates who are small for gestational age have transient hypoglycemia, which appears to be due to delayed induction of one or more gluconeogenic enzymes.
Ketotic hypoglycemia of childhood is a poorly understood syndrome that becomes evident between the ages of 1 and 5 years, remits before the age of 10 years, and is characterized by fasting hypoglycemia with normal suppression of insulin secretion. Because normal children develop hypoglycemia during fasts, these patients may simply represent one extreme of the normal distribution of glucose production during fasting.
Reactive hypoglycemia has been described in patients who have undergone gastrectomy or gastric bypass. Rapid absorption of ingested carbohydrate, together with enhanced secretion of gut factors that act as insulin secretagogues, is believed to cause marked hyperinsulinemia followed by hypoglycemia. Most descriptions of this disorder have relied on the oral glucose tolerance test for diagnosis. Whether, and how often, hypoglycemia after ordinary meals develops in such patients is unclear.
Patients with the rare enzymatic defects galactosemia and hereditary fructose intolerance have vomiting and reactive hypoglycemia after meals containing these sugars. Other manifestations include hepatomegaly and jaundice. These disorders usually become apparent in childhood. With these rare exceptions, the existence of reactive hypoglycemia, as a disorder distinct from fasting hypoglycemia, has not been convincingly shown.
THE HYPOGLYCEMIC STATES
- Differential Diagnosis
- Hypoglycemia due to Pancreatic B cell tumors
L General Considerations
L Clinical Findings
- Persistent Islet Hyperplasia
- Hypoglycemia Due to Extrapancreatic Tumors
- Postprandial Hypoglycemia (Reactive Hypoglycemia)
L Postgastrectomy Alimentary Hypoglycemia
L Functional Alimentary Hypoglycemia
L Late Hypoglycemia (Occult Diabetes)
- Alcohol-Related Hypoglycemia
L Fasting Hypoglycemia after Ethanol
L Postethanol Reactive Hypoglycemia
- Factitious Hypoglycemia
- Immunopathologic Hypoglycemia
- Drug-Induced Hypoglycemia