There are many causes of hypoglycemia (Table 420-1). Because hypoglycemia is common in insulin- or insulin secretagogue–treated diabetes, it is often reasonable to assume that a clinically suspicious episode is the result of hypoglycemia. On the other hand, because hypoglycemia is rare in the absence of relevant drug-treated diabetes, it is reasonable to conclude that a hypoglycemic disorder is present only in patients in whom Whipple’s triad can be demonstrated.
Particularly when patients are ill or medicated, the initial diagnostic focus should be on the possibility of drug involvement and then on critical illnesses, hormone deficiency, or non–islet cell tumor hypoglycemia. In the absence of any of these etiologic factors and in a seemingly well individual, the focus should shift to possible endogenous hyperinsulinism or accidental, surreptitious, or even malicious hypoglycemia.
Insulin and insulin secretagogues suppress glucose production and stimulate glucose utilization. Ethanol blocks gluconeogenesis but not glycogenolysis. Thus, alcohol-induced hypoglycemia typically occurs after a several-day ethanol binge during which the person eats little food, with consequent glycogen depletion. Ethanol is usually measurable in blood at the time of presentation, but its levels correlate poorly with plasma glucose concentrations. Because gluconeogenesis becomes the predominant route of glucose production during prolonged hypoglycemia, alcohol can contribute to the progression of hypoglycemia in patients with insulin-treated diabetes.
Many other drugs have been associated with hypoglycemia. These include commonly used drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, β-adrenergic receptor antagonists, quinolone antibiotics, indomethacin, quinine, and sulfonamides.
Among hospitalized patients, serious illnesses such as renal, hepatic, or cardiac failure; sepsis; and inanition are second only to drugs as causes of hypoglycemia.
Rapid and extensive hepatic destruction (e.g., toxic hepatitis) causes fasting hypoglycemia because the liver is the major site of endogenous glucose production. The mechanism of hypoglycemia in patients with cardiac failure is unknown. Hepatic congestion and hypoxia may be involved. Although the kidneys are a source of glucose production, hypoglycemia in patients with renal failure is also caused by the reduced clearance of insulin and the reduced mobilization of gluconeogenic precursors in renal failure.
Sepsis is a relatively common cause of hypoglycemia. Increased glucose utilization is induced by cytokine production in macrophage-rich tissues such as the liver, spleen, and lung. Hypoglycemia develops if glucose production fails to keep pace. Cytokine-induced inhibition of gluconeogenesis in the setting of nutritional glycogen depletion, in combination with hepatic and renal hypoperfusion, may also contribute to hypoglycemia.
Hypoglycemia can be seen with starvation, perhaps because of loss of whole-body fat stores and subsequent depletion of gluconeogenic precursors (e.g., amino acids), necessitating increased glucose utilization.
Neither cortisol nor growth hormone is critical to the prevention of hypoglycemia, at least in adults. Nonetheless, hypoglycemia can occur with prolonged fasting in patients with primary adrenocortical failure (Addison’s disease) or hypopituitarism. Anorexia and weight loss are typical features of chronic cortisol deficiency and likely result in glycogen depletion. Cortisol deficiency is associated with impaired gluconeogenesis and low levels of gluconeogenic precursors; these associations suggest that substrate-limited gluconeogenesis, in the setting of glycogen depletion, is the cause of hypoglycemia. Growth hormone deficiency can cause hypoglycemia in young children. In addition to extended fasting, high rates of glucose utilization (e.g., during exercise or in pregnancy) or low rates of glucose production (e.g., after alcohol ingestion) can precipitate hypoglycemia in adults with previously unrecognized hypopituitarism.
Hypoglycemia is not a feature of the epinephrine-deficient state that results from bilateral adrenalectomy when glucocorticoid replacement is adequate, nor does it occur during pharmacologic adrenergic blockade when other glucoregulatory systems are intact. Combined deficiencies of glucagon and epinephrine play a key role in the pathogenesis of iatrogenic hypoglycemia in people with insulin-deficient diabetes, as discussed earlier. Otherwise, deficiencies of these hormones are not usually considered in the differential diagnosis of a hypoglycemic disorder.
Fasting hypoglycemia, often termed non–islet cell tumor hypoglycemia, occurs occasionally in patients with large mesenchymal or epithelial tumors (e.g., hepatomas, adrenocortical carcinomas, carcinoids). The glucose kinetic patterns resemble those of hyperinsulinism (see next), but insulin secretion is suppressed appropriately during hypoglycemia. In most instances, hypoglycemia is due to overproduction of an incompletely processed form of insulin-like growth factor II (“big IGF-II”) that does not complex normally with circulating binding proteins and thus more readily gains access to target tissues. The tumors are usually apparent clinically, plasma ratios of IGF-II to IGF-I are high, and free IGF-II levels (and levels of pro-IGF-II [1–21]) are elevated. Curative surgery is seldom possible, but reduction of tumor bulk may ameliorate hypoglycemia. Therapy with a glucocorticoid, a growth hormone, or both has also been reported to alleviate hypoglycemia. Hypoglycemia attributed to ectopic IGF-I production has been reported but is rare.
Hypoglycemia due to endogenous hyperinsulinism can be caused by (1) a primary β-cell disorder—typically a β-cell tumor (insulinoma), sometimes multiple insulinomas, or a functional β-cell disorder with β-cell hypertrophy or hyperplasia; (2) an antibody to insulin or to the insulin receptor; (3) a β-cell secretagogue such as a sulfonylurea; or perhaps (4) ectopic insulin secretion, among other very rare mechanisms. None of these causes is common.
The fundamental pathophysiologic feature of endogenous hyperinsulinism caused by a primary β-cell disorder or an insulin secretagogue is the failure of insulin secretion to fall to very low levels during hypoglycemia. This feature is assessed by measurement of plasma insulin, C-peptide (the connecting peptide that is cleaved from proinsulin to produce insulin), proinsulin, and glucose concentrations during hypoglycemia. Insulin, C-peptide, and proinsulin levels need not be high relative to normal, euglycemic values; rather, they are inappropriately high in the setting of a low plasma glucose concentration. Critical diagnostic findings are a plasma insulin concentration ≥3 μU/mL (≥18 pmol/L), a plasma C-peptide concentration ≥0.6 ng/mL (≥0.2 nmol/L), and a plasma proinsulin concentration ≥5.0 pmol/L when the plasma glucose concentration is <55 mg/dL (<3.0 mmol/L) with symptoms of hypoglycemia. A low plasma β-hydroxybutyrate concentration (≤2.7 mmol/L) and an increment in plasma glucose level of >25 mg/dL (>1.4 mmol/L) after IV administration of glucagon (1.0 mg) indicate increased insulin (or IGF) actions.
The diagnostic strategy is (1) to measure plasma glucose, insulin, C-peptide, proinsulin, and β-hydroxybutyrate concentrations and to screen for circulating oral hypoglycemic agents during an episode of hypoglycemia and (2) to assess symptoms during the episode and seek their resolution following correction of hypoglycemia by IV injection of glucagon (i.e., to document Whipple’s triad). This is straightforward if the patient is hypoglycemic when seen. Since endogenous hyperinsulinemic disorders usually, but not invariably, cause fasting hypoglycemia, a diagnostic episode may develop after a relatively short outpatient fast. Serial sampling during an inpatient diagnostic fast of up to 72 h or after a mixed meal is more problematic. An alternative is to give patients a detailed list of the required measurements and ask them to present to an emergency room, with the list, during a symptomatic episode. Obviously, a normal plasma glucose concentration during a symptomatic episode indicates that the symptoms are not the result of hypoglycemia.
An insulinoma—an insulin-secreting pancreatic islet β-cell tumor—is the prototypical cause of endogenous hyperinsulinism and therefore should be sought in patients with a compatible clinical syndrome. However, insulinoma is not the only cause of endogenous hyperinsulinism. Some patients with fasting endogenous hyperinsulinemic hypoglycemia have diffuse islet involvement with β-cell hypertrophy and sometimes hyperplasia. This pattern is commonly referred to as nesidioblastosis, although β-cells budding from ducts are not invariably found. Other patients have a similar islet pattern but with postprandial hypoglycemia, a disorder termed noninsulinoma pancreatogenous hypoglycemia. Postgastric bypass postprandial hypoglycemia, which most often follows Roux-en-Y gastric bypass, is also characterized by diffuse islet involvement and endogenous hyperinsulinism. Some have suggested that exaggerated GLP-1 responses to meals cause hyperinsulinemia and hypoglycemia, but the relevant pathogenesis has not been clearly established. If medical treatments with agents such as an α-glucosidase inhibitor, diazoxide, or octreotide fail, partial pancreatectomy may be required. Autoimmune hypoglycemias include those caused by an antibody to insulin that binds post-meal insulin and then gradually disassociates, with consequent late postprandial hypoglycemia. Alternatively, an insulin receptor antibody can function as an agonist. The presence of an insulin secretagogue, such as a sulfonylurea or a glinide, results in a clinical and biochemical pattern similar to that of an insulinoma but can be distinguished by the presence of the circulating secretagogue. Finally, there are reports of very rare phenomena such as ectopic insulin secretion, a gain-of-function insulin receptor mutation, and exercise-induced hyperinsulinemia.
Insulinomas are uncommon, with an estimated yearly incidence of 1 in 250, 000. Because more than 90% of insulinomas are benign, they are a treatable cause of potentially fatal hypoglycemia. The median age at presentation is 50 years in sporadic cases, but the tumor usually presents in the third decade when it is a component of multiple endocrine neoplasia type 1 (Chap. 408). More than 99% of insulinomas are within the substance of the pancreas, and the tumors are usually small (<2.0 cm in diameter in 90% of cases). Therefore, they come to clinical attention because of hypoglycemia rather than mass effects. CT or MRI detects ∼70–80% of insulinomas. These methods detect metastases in the roughly 10% of patients with a malignant insulinoma. Transabdominal ultrasound often identifies insulinomas, and endoscopic ultrasound has a sensitivity of ∼90%. Somatostatin receptor scintigraphy is thought to detect insulinomas in about half of patients. Selective pancreatic arterial calcium injections, with the endpoint of a sharp increase in hepatic venous insulin levels, regionalize insulinomas with high sensitivity, but this invasive procedure is seldom necessary except to confirm endogenous hyperinsulinism in the diffuse islet disorders. Intraoperative pancreatic ultrasonography almost invariably localizes insulinomas that are not readily palpable by the surgeon. Surgical resection of a solitary insulinoma is generally curative. Diazoxide, which inhibits insulin secretion, or the somatostatin analogue octreotide can be used to treat hypoglycemia in patients with unresectable tumors; everolimus, an mTOR (mammalian target of rapamycin) inhibitor, is promising.