Evaluation of Hypoglycemia

David M. Slovik

“Hypoglycemia” is a term commonly used by patients to describe nonspecific symptoms they attribute to having a “low blood sugar” (e.g., irritability, fatigue, sweats, confusion, palpitations, tremulousness). In most instances, such symptoms bear little relation to blood sugar and do not qualify as bona fide hypoglycemia. Except in cases of diabetes, the workup of true hypoglycemia is an exercise in ruling out rare but important underlying pathology. At other times, the assessment is precipitated by the chance finding of a low blood glucose level. In the setting of diabetes, tight glucose control leading to hypoglycemic episodes is common and readily confirmed (see Chapter 102). In patients who do not have diabetes, confirmation may be more problematic, made so by a lack of glucose measurements taken during symptomatic periods and the nonspecific nature of the hypoglycemic symptoms. Compounding the diagnostic problem are unaddressed manifestations of psychopathology, which the patient may prefer to attribute to “hypoglycemia.” Although true hypoglycemia in the absence of diabetes is rarely encountered in the office setting, its causes include serious, treatable conditions that must not be missed. These factors make the workup of hypoglycemia challenging. The primary care physician needs to know how to differentiate suspected from true hypoglycemia and, in the nondiabetic patient, how to identify the rare case that requires an in-depth search for serious underlying disease. A cost-efficient strategy for assessment is needed because the question of hypoglycemia comes up so often.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18)

Mechanisms

Hypoglycemia can result from increased insulin secretion, enhanced glucose utilization, or inadequate functioning of one or more compensatory regulatory mechanisms (e.g., glucagon, epinephrine, growth hormone, and cortisol). When hypoglycemia occurs, the liver responds with increased glycogenolysis and gluconeogenesis, stimulated by glucagon and epinephrine, which activate hepatic phosphorylase. In addition, the pituitary secretes growth hormone, which inhibits the utilization of glucose by muscle and enhances lipolysis, and adrenocorticotropic hormone (ACTH), which promotes cortisol production. The increased cortisol acts to stimulate gluconeogenesis and diminish muscle uptake of glucose.

No single threshold of glucose concentration invariably triggers hypoglycemic symptoms or characterizes patients with a disorder of glucose homeostasis. Glucose levels lower than 45 mg/dL (2.5 mmol/L) have been documented in metabolically normal men during prolonged exercise and in healthy, asymptomatic women. More than 20% of normal patients demonstrate serum sugar levels less than 50 mg/dL during glucose tolerance testing. Conversely, hypoglycemic thresholds may rise in poorly controlled diabetes, in which levels as high as 75 mg/dL (4.3 mmol/L) may trigger symptoms, especially if there is a rapid decline in blood glucose levels. This has led to the view that the onset of hypoglycemic symptoms is related to the robustness of counterregulatory responses in addition to the rate of fall in serum glucose and the absolute serum glucose concentration. In patients with tightly controlled insulin-dependent diabetes, the catecholamine response is blunted, and they may exhibit few symptoms until their glucose concentration falls to a very low level.

Clinical Manifestations of Hypoglycemia and Its Etiologies

Hypoglycemic symptoms are typically categorized as neuroglycopenic (fatigue, drowsiness, lethargy, visual disturbances, behavioral and cognitive changes, impaired performance of routine tasks, confusion, loss of consciousness) or catecholamine mediated (sweating, anxiety, tremulousness, headache, palpitations, tachycardia). Adrenergic symptoms characteristically accompany acute, rapid falls in blood sugar, especially if levels drop to concentrations below 40 mg/dL. Neuroglycopenic symptoms can develop in the absence of premonitory adrenergic complaints. Symptoms suggestive of hypoglycemia can be ascribed to hypoglycemia only if they occur at a time of documented hypoglycemia and are relieved by the administration of glucose.

In the outpatient setting, most nondiabetes-related cases of true hypoglycemia occur among persons who look well. Their condition is a consequence of insulin excess, and they may have no apparent symptoms indicative of the underlying cause. Those cases resulting from a failure of counterregulatory mechanisms usually occur in very ill patients, who are typically hospitalized with end-stage disease.

Exogenous Insulin or Insulin Secretagogues

Use of exogenous insulin or insulin secretagogues (sulfonylureas, meglitinides) accounts for most of the hypoglycemia seen in clinical practice, usually in the context of attempting tight glycemic control of diabetes. Although the hypoglycemia associated with diabetic therapy may occur at any time in relation to meals, it tends to be most severe in the fasting state, after exercise or when meals are delayed or missed. The hypoglycemia associated with the use of potent, long-acting oral agents can be particularly severe and prolonged (see Chapter 102). Surreptitious administration of insulin or oral hypoglycemic agents is seen among self-destructive persons, prototypically health care workers with access to diabetic medications and syringes. Patients injecting insulin secretly may have high levels of immunoreactive insulin but very low serum levels of proinsulin and C-peptide (formed as part of proinsulin and split during endogenous synthesis) because they produce little endogenous insulin. However, those taking excessive doses of oral insulin secretagogues have high levels of insulin and C-peptide because the drugs stimulate endogenous insulin secretion. The diagnosis requires finding excessive amounts of oral agent and oral-agent metabolites in the plasma or urine.

Early Adult-Onset Diabetes

Postprandial hypoglycemia may occur 3 to 5 hours after meals as a consequence of delayed insulin release, a characteristic feature of type 2 diabetes. Insulin levels may be inappropriately high for the level of serum glucose at hand. In most type 2 diabetic patients, the mismatching of insulin and serum glucose levels is not sufficient to cause true symptomatic hypoglycemia, but on occasion, it may be noted.

Insulinomas

These rare but important causes of uncontrolled insulin production account for the large majority of patients with truly endogenous hyperinsulinemia. More than 85% of insulinomas are
benign islet cell tumors. Many occur in the setting of multiple endocrine neoplasia type 1 (MEN1), which also includes parathyroid hyperplasia and pituitary adenoma. The clinical presentation of insulinomas can be confusing and highly variable in timing and severity. The only valid generalizations are that fasting and exercise may precipitate symptoms and that profound degrees of hypoglycemia may ensue (leading to seizures in 10% of cases). Levels of serum glucose are not always low after an overnight fast. In a series of 39 patients with proven islet cell tumors, about half still had glucose levels greater than 60 mg/dL after 10 hours of fasting. Another series found symptoms to occur with equal frequency early in the morning, late in the afternoon, and several hours after a meal. Nonetheless, evidence of hyperinsulinism is evident in more than 75% of patients after 24 hours of fasting, and 80% report a combination of neuroglycopenic and adrenergic symptoms. Serum levels of insulin and C-peptide are high.

Other Causes of Endogenous Hyperinsulinemia

Functional beta-cell disorders include noninsulinoma pancreatogenous hypoglycemia syndrome, which is characterized by spells of neuroglycopenia due to endogenous hyperinsulinemia hypoglycemia typically after a meal. It is more common in men. The pancreatic abnormality is diffuse islet hypertrophy (nesidioblastosis). In addition, post-gastric bypass hypoglycemia is in this category along with autoimmune hypoglycemia, a rare cause of hypoglycemia with antibodies to insulin or the insulin receptor.

Non-Islet Cell Tumors

Some large mesenchymal tumors, hepatomas, gastric cancers, and adrenocortical carcinomas synthesize and release large amounts of the prohormone form of insulinlike growth factor II (big IGF-II). IGF-II inhibits the uptake of glucose by the liver and increases glucose uptake by the tumor itself and by insulin-responsive tissues (e.g., muscle and fat); hypoglycemia is the result. Insulin secretion is suppressed, so levels of immunoreactive insulin in the serum become very low. The presentation is that of hypoglycemia in the setting of a known malignancy. Rarely, the tumor may be silent, but usually, its presence dominates the clinical picture. Serum insulin and C-peptide levels are low. IGF-II may be detected in the serum in elevated quantities. Reduction in tumor bulk alleviates the hypoglycemia.

Defects in Glycogenolysis or Gluconeogenesis

Such defects are uncommon in the office setting; they are seen predominantly among very sick and often hospitalized patients with pituitary or adrenal insufficiency, end-stage liver or renal disease, or severe HIV infection. The common pathophysiologic denominator is failure of glucose counterregulatory mechanisms to maintain glucose homeostasis. Symptoms may be exacerbated by poor nutritional intake and substance abuse. For example, symptomatic hypoglycemia may be noted after severe alcoholic binge drinking in the absence of food intake. Ill patients are particularly sensitive to the hypoglycemic effects of drugs, including pentamidine when given for Pneumocystis pneumonia, gatifloxacin for infection, trimethoprim/sulfamethoxazole in the setting of renal failure, quinine or quinidine in the setting of malaria, and propoxyphene in renal failure. Salicylates, beta-blockers, indomethacin, and haloperidol can also cause non-insulin-related hypoglycemia.

True Reactive Hypoglycemia (after Gastric Surgery)

Onset of true hypoglycemia 1 to 2 hours after eating characterizes the reactive hypoglycemia of patients who have undergone gastric surgery. About 5% to 10% of such patients experience a reactive hypoglycemia, which is believed to be related to pyloric sphincter incompetence and the excessively rapid entry of concentrated carbohydrates into the small bowel. Unidentified gut factors are stimulated, causing the release of excessive insulin. Symptoms should not be confused with those of the dumping syndrome (see Chapter 64), which consist of nausea, fullness, and weakness developing within an hour after eating. An occasional patient with a functional defect in gastric emptying may present in similar fashion.

Functional Reactive “Hypoglycemia”

This common postprandial syndrome is characterized by autonomic hypoglycemia-like symptoms occurring within 2 to 4 hours after a meal and relieved or prevented by a snack. Patients may report that symptoms are especially likely to occur with the intake of concentrated sweets. Some authorities argue that the designation of “functional reactive hypoglycemia” is inappropriate because the serum glucose is usually normal at the time symptoms occur, failing the diagnostic criteria for true hypoglycemia (see later discussion). Insulin secretion is normal, and no relation between glucose levels and symptoms can be demonstrated. The pathophysiology of this alimentary variant is unknown, but it may respond to a high-protein, low-carbohydrate diet. The “functional reactive hypoglycemia” label is also sometimes applied inappropriately to asymptomatic patients who manifest a low serum glucose during a 5-hour glucose tolerance test, a normal occurrence in 10% to 20% of healthy persons.

DIFFERENTIAL DIAGNOSIS (2,5,9,18)

The main differential diagnostic issue for the primary care physician is less about distinguishing among the causes of true hypoglycemia than about confirming its presence because “hypoglycemic” symptoms are quite nonspecific and more often due to etiologies other than true hypoglycemia. Two important groups of nonhypoglycemic patients must be differentiated from patients who manifest genuine falls in glucose in conjunction with symptoms: (a) The first group comprises persons with anxiety or depression who have multiple bodily complaints of a functional or psychophysiologic nature (see Chapters 226 and 227). Such patients commonly complain of fatigue, headache, muscle spasms, palpitations, numbness, sweating, and mental dullness and often show manifestations of a somatization disorder (see Chapter 230). They may attribute their symptoms to “hypoglycemia,” which conveniently explains their difficulties but promotes avoidance of the psychosocial issues at hand. Requests for glucose tolerance testing are frequent. (b) The second group is bothered by postprandial symptoms in the context of normal serum glucose levels, experiencing symptoms that are very similar to those experienced by patients with truly reactive hypoglycemia.

Once true hypoglycemia is identified, attention turns to its causes. The traditional classification of etiologies for hypoglycemia (“fasting” vs. “reactive”) is fading from use because truly reactive hypoglycemia does not occur except in patients who have undergone gastric surgery, and fasting hypoglycemia can also occur postprandially. More-modern etiologic classifications use pathogenetic and clinical categories such as “insulin related versus non-insulin related” and “healthy versus ill appearing” (Table 97-1).

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