INTRODUCTION — In patients without diabetes, hypoglycemia is a clinical syndrome with diverse causes in which low plasma glucose concentrations lead to symptoms and signs, which resolve when the plasma glucose concentration is raised. This topic will review the clinical manifestations, diagnosis, and causes of clinical hypoglycemia. The evaluation of patients with hypoglycemia, treatment of specific causes, and hypoglycemia in patients with diabetes are reviewed elsewhere. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach" and "Insulinoma" and "Factitious hypoglycemia" and "Nonislet cell tumor hypoglycemia" and "Hypoglycemia in adults with diabetes mellitus".)
Patients who have only sympathoadrenal symptoms (anxiety, weakness, tremor, perspiration, or palpitations) but normal concurrent plasma glucose concentrations have a low probability of having a hypoglycemic disorder. This combination of normal glucose in the face of sympathoadrenal symptoms occurs most commonly in the postprandial state. (See "Evaluation of postprandial symptoms of hypoglycemia in adults without diabetes", section on 'Postprandial syndrome'.)
EPIDEMIOLOGY — Hypoglycemia is uncommon in individuals who do not have drug-treated diabetes mellitus [1-3]. In a retrospective review of 37,898 nondiabetic, noncritical care hospital admissions, the estimated frequency of hypoglycemia (≤55 mg/dL [3 mmol/L]) was 36 per 10,000 admissions [4]. In these patients, hypoglycemia was caused by a variety of nondiabetes drugs, alcohol, and critical illnesses such as hepatic, renal, or cardiac failure, sepsis, or inanition. Most patients had multiple possible reasons for hypoglycemia. Only seven patients had unexplained hypoglycemia, which did not recur during the inpatient admission. There are few data on the frequency of unexplained hypoglycemia in the outpatient setting.
CLINICAL MANIFESTATIONS
Symptoms — The symptoms of hypoglycemia (in patients with and without diabetes) are nonspecific. Hypoglycemia causes autonomic and neuroglycopenic symptoms. In studies of insulin-induced hypoglycemia in healthy volunteers, the following findings were noted [5,6]:
●Autonomic symptoms included tremor, palpitations, and anxiety/arousal (catecholamine-mediated, adrenergic) and sweating, hunger, and paresthesias (acetylcholine-mediated, cholinergic).
●Neuroglycopenic symptoms included dizziness, weakness, drowsiness, and confusion or altered mental status.
In a case series of patients with insulinoma, approximately 77 percent of patients presented with autonomic symptoms and 96 percent with neuroglycopenic symptoms; ≥80 percent had confusion or abnormal behavior, 50 percent had unconsciousness or amnesia, and 12 to 19 percent had grand mal seizures [7,8].
In the patient without diabetes, the occurrence of neuroglycopenic symptoms provides clinically compelling evidence of an underlying hypoglycemic disorder. The character of the hypoglycemia symptoms is usually consistent from episode to episode, they may occur in the fasting or postprandial state [9], and the symptoms may not be recognized by the patient, even though they are evident to an observer. Many cannot describe their episodes in any detail because of amnesia, so that information should be obtained from a close family member or friend whenever possible. It is also important to appreciate that patients sometimes cannot differentiate the occurrence of symptoms in the fasting versus postprandial period.
Some degree of hypoglycemia unawareness may occur in hypoglycemic patients without diabetes, particularly patients with recent antecedent hypoglycemia [10]. In these patients, the typical symptoms may be altered or absent. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus", section on 'Hypoglycemia-associated autonomic failure'.)
Signs — Diaphoresis and pallor are common signs of hypoglycemia [11]. Heart rates and systolic blood pressures are raised but not greatly. Neuroglycopenic manifestations (eg, cognitive impairment, behavioral changes, psychomotor abnormalities) are often observable. Occasionally, transient neurologic deficits occur. Permanent neurologic damage is rare and, should it occur, it would be more likely in a patient with diabetes and prolonged severe hypoglycemia.
Laboratory findings — The lower limit of the normal fasting plasma glucose value is typically 70 mg/dL (3.9 mmol/L). However, lower values can be encountered in healthy individuals, especially during prolonged fasting when insulin secretion appropriately declines and fat increasingly supplants glucose as a fuel of choice. In this setting, glucose can decrease to the 50 mg/dL (2.8 mmol/L) range and, in a normal fast, is accompanied by normal cognitive function and an elevation in ketone bodies such as beta-hydroxybutyrate. If insulin secretion does not appropriately decline (eg, due to exogenous insulin administration, insulinoma), the transition to fat as a fuel source is inhibited, there is no elevation in beta-hydroxybutyrate, and symptomatic hypoglycemia can occur. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on '72-hour fast'.)
The onset of symptoms of hypoglycemia normally occur as glucose levels fall below 55 mg/dL (3 mmol/L), although the specific value varies among and within individuals over time. Glucose counterregulation (eg, release of glucagon and epinephrine) can be detected at levels approximately 10 mg/dL higher, before the onset of symptoms of hypoglycemia. However, the glycemic thresholds for these counterregulatory responses shift to higher plasma glucose concentrations in patients with poorly controlled diabetes and to lower plasma glucose concentrations in patients with repeated episodes of hypoglycemia, such as may be caused by intensive therapy of diabetes [12] or an insulinoma [10]. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus", section on 'Counterregulatory hormones'.)
DIAGNOSIS — In a person without diabetes, the presence of a hypoglycemic disorder cannot be diagnosed with confidence solely on the basis of a low plasma glucose concentration [11]. Similarly, patients who have only sympathoadrenal symptoms (anxiety, weakness, tremor, perspiration, or palpitations), but normal concurrent plasma glucose concentrations, and resolution of symptoms after dietary modification have a low probability of having a hypoglycemic disorder. (This combination is most common in patients with postprandial symptoms.) (See "Evaluation of postprandial symptoms of hypoglycemia in adults without diabetes", section on 'Postprandial syndrome'.)
Although autonomic and neuroglycopenic symptoms may be highly suggestive of hypoglycemia, they cannot be ascribed to hypoglycemia with confidence unless the plasma glucose concentration is low at the same time and the symptoms are relieved when it is raised [11]. This triad of symptoms, a low plasma glucose concentration, and relief by raising plasma glucose, was coined by Whipple in 1938 and bears his name, Whipple's triad [13]:
●Recognize that the patient's symptoms could be caused by hypoglycemia; symptoms of neuroglycopenia are the most specific
●Document that the patient's plasma glucose concentration is low when the symptoms are present
●Demonstrate that the symptoms are relieved by correction of the hypoglycemia by administration of glucose or glucagon
A hypoglycemic disorder should be diagnosed only in those in whom Whipple's triad is documented, and only those patients in whom Whipple's triad is documented require evaluation and management of hypoglycemia (see "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Approach to testing'). However, reliably measured, severely depressed venipuncture plasma glucose concentrations (<40 mg/dL [2.2 mmol/L]) in the absence of symptoms should not be ignored. This may occur in patients with repeated episodes of hypoglycemia or artifactual hypoglycemia. (See 'Differential diagnosis' below.)
Although low blood glucose values measured using reflectance meters or continuous glucose monitoring (CGM) devices suggest the presence of hypoglycemia, these methods are not reliable to diagnose hypoglycemia in the absence of insulin or insulin secretagogue treatment of diabetes [14]. A patient who has a single low blood glucose value measured by a meter but no symptoms of hypoglycemia probably does not need further evaluation; on the other hand, evaluation is indicated in a patient who has repeated low values and accompanying symptoms with a reflectance meter or with a CGM device. Reflectance meters and CGM may be inaccurate in the lower range of glycemia, and therefore, low values should be confirmed with laboratory testing. Beyond raising the suspicion of a hypoglycemic disorder, reflectance meters and CGM should not be used in the diagnostic work-up of hypoglycemic disorders. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach".)
DIFFERENTIAL DIAGNOSIS
●Low glucose, asymptomatic – A low venipuncture plasma glucose concentration in the absence of symptoms of hypoglycemia suggests either a physiologically normal "low" glucose, for example, after a prolonged fast; the possibility of shifted glycemic thresholds, as may occur in patients with repeated episodes of hypoglycemia (impaired awareness of hypoglycemia); or artifactual hypoglycemia [6,11]. The artifactual hypoglycemia can occur if an antiglycolytic agent (such as fluoride) is not present in the blood collection tube and processing is delayed, particularly in samples from patients with leukemia, in which the large numbers of leukocytes consume glucose, and in samples from patients with severe hemolytic disease or erythrocytosis, in which the nucleated red blood cells or erythrocytes consume glucose [15-18]. This problem tends to be greater if glucose is measured in serum and the blood sample is not processed promptly.
Reliably measured low plasma glucose concentrations should not be ignored. The measurement should be repeated using a collection tube that contains an inhibitor of glycolysis, and processing should not be delayed. Ideally, whole blood samples should be drawn into tubes with sodium fluoride, kept on ice, and centrifuged quickly to separate plasma from erythrocytes.
For the rare patient without diabetes having repeated episodes of asymptomatic hypoglycemia (<40 mg/dL [2.2 mmol/L]) and in whom artifactual hypoglycemia has been ruled out, further evaluation to assess the genesis of the hypoglycemia is necessary. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Approach to testing'.)
●Normal glucose, symptomatic – An unequivocally normal (>70 mg/dL [3.9 mmol/L]) plasma glucose concentration that was obtained during autonomic symptoms (tremor, palpitations, anxiety, sweating, hunger) is not consistent with a hypoglycemic disorder [1]. The differential diagnosis of autonomic symptoms is extensive and includes postprandial syndrome, cardiac disease (arrhythmia, valvular heart disease), medications, psychiatric disease, and metabolic disorders (hyperthyroidism, pheochromocytoma). (See "Evaluation of postprandial symptoms of hypoglycemia in adults without diabetes", section on 'Postprandial syndrome' and "Evaluation of palpitations in adults" and "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Overview of the clinical manifestations of hyperthyroidism in adults".)
CLASSIFICATION AND CAUSES — Hypoglycemia may be classified as insulin mediated or non-insulin mediated, or fasting or postprandial. The insulin-based classification deals with pathogenesis but not cause. The latter classification is descriptive and may be useful for communicating the timing of symptoms but provides little definitive clues as to the etiology of the underlying hypoglycemia. This is because hypoglycemic disorders once thought to cause exclusively postprandial or fasting hypoglycemia have been observed in some cases to cause hypoglycemia in the alternate state. In a retrospective review of 237 patients with surgically confirmed insulinoma, 21 percent reported both fasting and postprandial symptoms and 6 percent reported only postprandial symptoms [9].
A classification that is more useful clinically is one based upon whether the patient appears to be ill (or is medicated) or is seemingly well [2,11]. The context in which hypoglycemia occurs (ie, in a hospitalized patient versus in the outpatient setting) provides similar information. The major causes of hypoglycemia using this classification are listed in the table (table 1). Given documentation of Whipple's triad, detailed evaluation is usually required in a healthy-appearing patient, whereas hypoglycemia may be readily recognized as part of the underlying illness or its treatment in an ill or medicated patient [11]. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Candidates for evaluation'.)
Hospitalized patients can present unique diagnostic challenges. In them, hypoglycemia, even in those with diabetes, is often multifactorial and iatrogenic. Therefore, it is as important to examine the patient's medical record (including the drug administration record) as it is to talk to and examine the patient.
Ill or medicated individuals
Drugs — Drugs are the most common cause of hypoglycemia [11]. In addition to insulin, sulfonylureas, and meglitinides, other drugs may also cause hypoglycemia (table 2). In a systematic review of 448 publications describing drug-induced hypoglycemia (excluding drugs used to treat diabetes and alcohol), 164 different drugs were associated with hypoglycemia [19]. However, the evidence supporting the majority of the associations was judged to be of very low quality. The drugs most commonly associated with hypoglycemia were quinolones, pentamidine, quinine, beta blockers, angiotensin-converting enzyme inhibitors, and insulin-like growth factor-1 (IGF-1).
The possible contribution of drugs in either ill or seemingly well individuals cannot be overemphasized. A thorough review of a patient's medication history is essential. Drug-induced hypoglycemia occurs more frequently in older patients with underlying renal or hepatic dysfunction and in those taking glucose-lowering medications, particularly insulin or sulfonylureas [20]. (See "Glycemic control in critically ill adult and pediatric patients".)
Ethanol — Ethanol inhibits gluconeogenesis but not glycogenolysis [11,21]. Thus, alcohol-induced hypoglycemia typically follows a several-day alcohol binge with limited ingestion of food, resulting in hepatic glycogen depletion. Ethanol may not be detectable in blood at the time of presentation. Because gluconeogenesis becomes the sole source of glucose production during prolonged hypoglycemia, alcohol can also contribute to the progression of hypoglycemia in patients with insulin-treated diabetes. Alcohol ingestion is often the cause of, or a contributing factor to, hypoglycemia in an emergency department.
Critical illness — Severe hypoglycemia can occur during critical illnesses [11]. In a retrospective study of hypoglycemia in an adult intensive care unit, independent risk factors for developing hypoglycemia included diabetes, septic shock, renal insufficiency, mechanical ventilation, severity of illness, and treatment with intensive insulin to achieve tight glycemic control [22].
Sepsis is a relatively common cause of hypoglycemia [11,23]. Cytokine-accelerated glucose utilization is usually matched by increased glucose production. Hypoglycemia develops when the latter fails to keep pace, perhaps because of cytokine-induced inhibition of gluconeogenesis in the setting of glycogen depletion [24,25]. The mechanism of hypoglycemia in chronic kidney disease is less clear. It likely involves impaired gluconeogenesis, reduced renal clearance of insulin, and reduced renal glucose production. In severe liver failure, gluconeogenesis is also impaired.
In tropical countries where malaria is endemic, hypoglycemia can result from malaria, its treatment, or both [11,19]. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)
Malnourishment — Malnutrition can cause hypoglycemia as a result of substrate limitation of gluconeogenesis and glycogenolysis in the setting of glycogen depletion. Hypoglycemia has been reported in patients with anorexia nervosa [26,27].
Cortisol deficiency — Hypoglycemia can also occur in patients with cortisol deficiency (Addison's disease) [11,28]. However, it is not often found in adults in the absence of diagnosed cortisol deficiency or other clinical clues suggesting that diagnosis. Hypoglycemia is more common in infants and children with primary adrenal insufficiency, patients with secondary adrenal insufficiency caused by isolated corticotropin (ACTH) deficiency, and patients with type 1 diabetes mellitus who develop adrenal insufficiency. In the last setting, sensitivity to insulin is increased because of loss of the gluconeogenic effect of cortisol and of the hyperglycemic effects of epinephrine. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)
Nonislet cell tumors — Hypoglycemia has been observed in a small number of patients with nonislet cell tumors, usually large, clinically obvious tumors of mesenchymal or epithelial cell types. Hypoglycemia usually occurs as a result of tumor production of an insulin-like growth factor (eg, incompletely processed IGF-2) [11]. Endogenous production of insulin is appropriately suppressed. The pathophysiology, diagnosis, and treatment of nonislet cell tumor hypoglycemia are reviewed in detail elsewhere. (See "Nonislet cell tumor hypoglycemia".)
Seemingly well individuals
Endogenous hyperinsulinism — Hyperinsulinemic hypoglycemia occurs when there is a failure of insulin secretion to fall appropriately in the setting of hypoglycemia; hypoglycemia is the result of low rates of glucose production rather than high rates of glucose utilization [29].
Endogenous hyperinsulinism is more likely in an otherwise overtly well individual with no clinical clues to the common causes of hypoglycemia. The diagnosis can be delayed for years. In adults, hypoglycemia due to endogenous hyperinsulinism can be caused by the following (table 1):
●A beta cell secretagogue, such as a sulfonylurea. (See 'Accidental, surreptitious, or malicious hypoglycemia' below.)
●A beta cell tumor. (See "Insulinoma".)
●A functional beta cell disorder that can occur as a feature of the noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS). (See "Noninsulinoma pancreatogenous hypoglycemia syndrome".)
●After gastric bypass or Nissen fundoplication when there is a mismatch between postprandial glucose disappearance and the offset of insulin action due to rapid transit of calories through the upper gastrointestinal tract [30,31].
●Insulin autoimmune hypoglycemia.
Insulin autoimmune hypoglycemia occurs in patients who have antibodies directed to endogenous insulin or to the insulin receptor. Symptoms can occur postprandially, fasting, or in both states. In patients with insulin antibody-mediated hypoglycemia, it is speculated that insulin, secreted in response to a meal, binds to the antibody and then disassociates in an unregulated fashion, causing hyperinsulinemia and hypoglycemia. In patients with antibodies to the insulin receptor, who usually have preexistent insulin-treated diabetes, hypoglycemia occurs as a result of antibody activation of the receptor [32].
Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infancy. PHHI is a genetic disorder with both familial and sporadic forms, characterized by dysregulation of insulin secretion. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)
Accidental, surreptitious, or malicious hypoglycemia — The possibility of accidental, surreptitious, or even malicious hypoglycemia should be considered when the cause of a hypoglycemic disorder is not apparent [11]. Hypoglycemia can result from medical, pharmacy, or patient errors, such as the mistaken use of a hypoglycemic tablet by an older spouse of a patient with diabetes. It may also occur after ingestion of herbal products contaminated with sulfonylureas [33] or after covert self-administration of a hypoglycemic tablet or insulin by a patient with or without diabetes.
Covert use of a glucose-lowering medication, often a sulfonylurea, occurs more commonly in a person who is knowledgeable about how the drug works and who has access to it. Malicious hypoglycemia involves administration of an insulin secretagogue or insulin to another person with the intent to cause hypoglycemia. (See "Factitious hypoglycemia".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Low blood sugar in people with diabetes (The Basics)" and "Patient education: Low blood sugar in people without diabetes (The Basics)")
SUMMARY
●Hypoglycemia is uncommon in individuals who do not have drug-treated diabetes mellitus. (See 'Epidemiology' above and "Hypoglycemia in adults with diabetes mellitus".)
●The symptoms of hypoglycemia (in patients with and without diabetes) are nonspecific and may include tremor, palpitations, sweating, hunger, paresthesias, cognitive impairment, behavioral changes, and psychomotor abnormalities. (See 'Clinical manifestations' above.)
●The diagnosis of hypoglycemia in patients without diabetes is based upon the presence of Whipple's triad: symptoms, signs, or both consistent with hypoglycemia; a low plasma glucose concentration at the time of symptoms; and resolution of those signs and symptoms after raising the plasma glucose concentration. (See 'Diagnosis' above.)
●A clinically useful classification of hypoglycemia is one based upon whether the patient appears to be ill (or is medicated) or is seemingly well. In individuals without diabetes but with concomitant illness, hypoglycemia is most often due to a drug (table 2). Less common causes include critical illness, endocrine deficiency, or a nonislet cell tumor. In the well-appearing patient, endogenous hyperinsulinism or accidental, surreptitious, or malicious hypoglycemia are more likely (table 1). (See 'Classification and causes' above.)
●The evaluation of hypoglycemia is reviewed elsewhere. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach".)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges F John Service, MD, PhD, now deceased, who contributed to an earlier version of this topic.
The UpToDate editorial staff also acknowledges Philip E Cryer, MD, who contributed to an earlier version of this topic review.
