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Harrison’s Manual of Medicine



Clinical Features

Glucose is an obligate metabolic fuel for the brain, making it particularly vulnerable to hypoglycemia. Counterregulatory responses to hypoglycemia include insulin suppression and the release of catecholamines, glucagon, growth hormone, and cortisol.
The laboratory diagnosis of hypoglycemia is usually defined as a plasma glucose level <2.5–2.8 mmol/L (<45–50 mg/dL), although the absolute glucose level at which symptoms occur varies among individuals. For this reason, Whipple’s triad should be present: (1) symptoms consistent with hypoglycemia, (2) a low plasma glucose concentration, and (3) relief of symptoms after the plasma glucose level is raised.
Hypoglycemia occurs most commonly as a result of treating patients with diabetes mellitus. However, a number of other disorders are also associated with hypoglycemia, and it is useful to divide these into those associated with fasting or the postprandial state.


Underproduction of glucose: hormone deficiencies (hypopituitarism and adrenal insufficiency), inherited enzyme defects, hepatic failure, renal failure, hypothermia, and drugs (ethanol, beta blockers, and rarely salicylates).

Overutilization of glucose: hyperinsulinism (exogenous insulin, sulfonylureas, insulin or insulin receptor antibodies, insulinoma, endotoxic shock, renal failure, and use of pentamidine, quinine, or disopyramide) and with appropriate insulin levels but increased levels of insulin-like growth factors such as IGF-II (mesenchymal or other extrapancreatic tumors and prolonged starvation).

Postprandial (reactive): after gastric surgery and in children with rare enzymatic defects.
Clinical Features
Symptoms of hypoglycemia can be divided into autonomic (adrenergic: palpitations, tremor, and anxiety; and cholinergic: sweating, hunger, and paresthesia) and neuroglycopenic (behavioral changes, confusion, fatigue, seizure, loss of consciousness, and, if hypoglycemia is severe and prolonged, death). Tachycardia, elevated systolic blood pressure, pallor, and diaphoresis may be present on physical examination.
Recurrent hypoglycemia shifts thresholds for the autonomic symptoms and counterregulatory responses to lower glucose levels, leading to hypoglycemic unawareness. Under these circumstances, the first manifestation of hypoglycemia is neuroglycopenia, placing patients at risk of being unable treat themselves.
Diagnosis of the hypoglycemic mechanism is critical for choosing a treatment that prevents recurrent hypoglycemia (Fig. 41-1). Urgent treatment is often necessary in patients with suspected hypoglycemia. Nevertheless, blood should be drawn at the time of symptoms, whenever possible before the administration of glucose, to allow documentation of the glucose level. If the glucose level is low and the cause of hypoglycemia is unknown, additional assays should be performed on blood obtained at the time of a low plasma glucose. These should include insulin, C-peptide, sulfonylurea levels, cortisol, and ethanol. In the absence of documented spontaneous hypoglycemia, overnight fasting or food deprivation during observation in the outpatient setting will sometimes elicit hypoglycemia and allow diagnostic evaluation. An extended (up to 72 h) fast under careful supervision in the hospital may otherwise be required—the test should be terminated if plasma glucose drops below 2.5 mmol/L (45 mg/dL) and the patient has symptoms.

FIGURE 41-1. Diagnostic approach to a patient with suspected hypoglycemia based on a history of symptoms, a low plasma glucose concentration, or both.

Interpretation of fasting test results is shown in Table 41-1.

Table 41-1 Diagnostic interpretation of hypoglycemia

The syndrome of hypoglycemic unawareness in patients with diabetes mellitus is reversible after as little as 2 weeks of scrupulous avoidance of hypoglycemia. This involves a shift of glycemic thresholds back to higher glucose concentrations.
Acute therapy of hypoglycemia requires administration of oral glucose or 25 g of a 50% solution intravenously followed by a constant infusion of 5 or 10% dextrose if parenteral therapy is necessary. Hypoglycemia from sulfonylureas is often prolonged, requiring treatment and monitoring for 24 h or more. Subcutaneous or intramuscular glucagon can be used in diabetics. Prevention of recurrent hypoglycemia requires treatment of the underlying cause of hypoglycemia, including discontinuation or dose reduction of offending drugs, replacement of hormonal deficiencies, treatment of critical illnesses, and surgery of insulinomas or other tumors. Treatment of other forms of hypoglycemia is dietary, with avoidance of fasting and ingestion of frequent small meals.


For a more detailed discussion, see Cryer PE: Hypoglycemia, Chap. 334, p. 2138, in HPIM-15.


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