ABSTRACT

Objective: To describe the evaluation and management of hypoglycemia in patients without diabetes mellitus. Methods: Review of the literature for the evaluation and management of non-diabetic hypoglycemia using Medline and PubMed. Results: Hypoglycemia (glucose <55 mg/dL [3.0 mmol/L]) is uncommon in people without diabetes. Whipple’s triad (low plasma glucose concentration, clinical signs/symptoms consistent with hypoglycemia, and resolution of signs or symptoms when the plasma glucose concentration increases) should be documented in patients prior to initiating an evaluation. Medications should be reviewed. Critical illnesses, malnutrition, hormone deficiencies especially adrenal insufficiency, and non-islet cell tumors secreting IGF-II need be considered in those who are ill. Hypoglycemia can also follow bariatric surgery. In apparently healthy individuals, endogenous hyperinsulinism due to insulinoma, functional β-cell disorders, or the insulin autoimmune syndrome are possible, as are accidental, surreptitious or factitious causes of hypoglycemia. Tests performed during hypoglycemia can establish the cause in those whom illness or medications are excluded. Testing should be done at the time of spontaneous development of symptoms. If this is not possible, it can be done in the setting of a prolonged supervised fast or during a mixed meal test. Endogenous hyperinsulinism is supported by insulin ≥3 uU/mL, c-peptide ≥0.2 nmol/L, proinsulin ≥5 pmol/L, β-hydroxybutyrate ≤2.7 mmol/L and undetectable sulfonylurea/meglitinide in the setting of hypoglycemia. The use of glucagon tolerance tests, c-peptide suppression tests, anti-insulin antibody testing, and continuous glucose monitoring are discussed. Congenital causes of hypoglycemia, diagnosed primarily in neonates and children, are also reviewed. Treatment of hypoglycemia is tailored to the etiology. Conclusions: Accurate diagnosis is needed to direct nutritional, medical, and/or surgical treatment for non-diabetic hypoglycemia. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Hypoglycemia is uncommon in older children and adults who are not being treated for diabetes mellitus, and may be due to varied or multiple etiologies. Different causes of hypoglycemia should be considered in adults who are apparently healthy compared to those who are ill. Whipple’s triad (low plasma glucose concentration, clinical signs or symptoms consistent with hypoglycemia, and resolution of signs or symptoms when the plasma glucose concentration increases) should be documented prior to initiating an evaluation (1-3). Appropriate blood tests performed at the time of hypoglycemia can establish the etiology in those for whom illness or medications are not a readily apparent cause. Testing should be done at the time of spontaneous development of symptoms when feasible. If this is not possible, testing can be performed in the setting of a prolonged supervised fast or during a mixed meal test as described in this review. Additional diagnostic tests are also discussed. Treatment of hypoglycemia should be tailored to its cause and may include dietary, medical, and/or surgical therapies. The diagnosis and evaluation of neonates and infants with hypoglycemia will also be briefly reviewed.

PHYSIOLOGY

Glucose is the solitary source of energy for the brain under normal conditions (4). In order to maintain proper brain function, plasma glucose must be maintained within a relatively narrow range. Redundant counter-regulatory mechanisms are in place to prevent or correct hypoglycemia. As glucose levels decline, major defense mechanisms include a decrease in insulin secretion, an increase in glucagon secretion, and an increase in epinephrine secretion. Increased cortisol and growth hormone secretion are observed during prolonged hypoglycemia. These hormonal changes cause a reduction in peripheral glucose utilization, an increase in hepatic glucose output (from glycogenolysis +/- gluconeogenesis), and an increase in the availability of alternative fuels. Protein breakdown produces a rise in levels of the gluconeogenic amino acids alanine and glutamine, and lipolysis results in a rise in plasma free fatty acids levels and urine and plasma ketone levels. The plasma concentration of β-hydroxybutyrate reflects ketogenesis.

If these defenses fail and plasma glucose levels continue to fall, symptoms prompting food ingestion will develop. Symptoms typically develop at a plasma glucose of 55 mg/dL (3.0 mmol/L) in otherwise healthy individuals (5-6). At glucose levels of 55 mg/dL (3.0 mmol/L) and lower, insulin secretion is normally almost completely suppressed. Lower plasma glucose levels occur in healthy individuals without symptoms or signs during extended fasting when there is use of alternative fuels such as ketones (1). Because of this variability there is not a single plasma glucose concentration that defines hypoglycemia. In type 1 and longstanding type 2 diabetes the counter-regulatory responses to hypoglycemia are frequently impaired and shift to lower thresholds (1,7-8), but these thresholds have not been as well studied in patients with chronic hypoglycemia in the absence of diabetes.

SIGNS AND SYMPTOMS

Low blood glucose concentrations lead to sympathoadrenergic activation and neuroglycopenia (6,9-11). Awareness of hypoglycemia is mainly due to the perception of neurogenic symptoms (12). Symptomatic hypoglycemia is diagnosed clinically using Whipple’s triad: symptoms of hypoglycemia, plasma glucose concentration <55 mg/dL (3.0 mmol/L), and resolution of those symptoms after the plasma glucose concentration is raised. The most common symptoms of hypoglycemia are listed in Table 1. The presence of neuroglycopenic symptoms in patients without diabetes is strongly suggestive of a hypoglycemic disorder (1). Conversely, there is a low likelihood of a hypoglycemia disorder in those with the presence of neurogenic symptoms in the absence of a low plasma glucose concentration (12). Capillary blood glucose measurements should not be used in the evaluation of hypoglycemia due to poor accuracy (1). Symptoms of hypoglycemia may be absent in patients with hypoglycemia unawareness which is thought to be due to a decreased sympathetic response related to recurrent hypoglycemia, prior exercise, or sleep (1,7-9).

DIFFERENTIAL DIAGNOSIS

In individuals with hypoglycemia in the absence of diabetes mellitus the differential diagnosis is broad (Table 2). Multiple etiologies may be present concurrently. Different causes of hypoglycemia should be considered in patients who are apparently healthy compared to those who are ill. Drugs, critical illnesses, hormone deficiencies, and non-islet cell tumors should be considered in those who are ill or taking medications. In apparently healthy individuals, endogenous hyperinsulinism due to insulinoma, functional β-cell disorders, or insulin autoimmune conditions are possible, as are accidental, surreptitious or factitious causes of hypoglycemia. Hypoglycemia in patients who have had bariatric surgery is increasingly recognized as the frequency of these operations has grown. Artifactual hypoglycemia can occur if blood samples are improperly handled (lack of antiglycolytic agent in the collection tube) and there is a delay in processing.

Drugs are the most common cause of hypoglycemia (Table 3) (1). Drug-induced hypoglycemia is more common in older patients with underlying comorbidities and in those taking glucose lowering medications, especially insulin, the sulfonylurea drugs glyburide, glipizide, and glimepiride, and the meglitinides (13-15). Accidental, surreptitious or malicious hypoglycemia due to administration of insulin or insulin secretagogues needs to be considered. Non-selective β blockers can impair hepatic and renal glucose output and have been associated with the development of hypoglycemia. Pentamidine can cause direct injury to pancreatic β cells, causing an acute release of insulin. Case reports also suggest that ACE inhibitors can cause hypoglycemia (16). Several mechanisms have been proposed. Using euglycemic glucose-clamp studies, enhanced insulin sensitivity during treatment with captopril was shown (17), Captopril can also reduce the insulin-induced rise in epinephrine and norepinephrine (18).

Quinolone use has been associated with the development of hypoglycemia. Case reports have described hypoglycemia in patients who were taking ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin. Gatifloxacin was withdrawn from the US market because of reports of severe hypoglycemia. The risk of hypoglycemia is increased in the setting of renal insufficiency or with the concomitant use of a sulfonylurea drug. There are data suggesting that fluoroquinolones, to varying degrees, increase insulin secretion by inhibiting the Kir6.2 subunit of the ATP-sensitive K+ channels in pancreatic β cells (19).

Deficiencies in counter-regulatory hormones (cortisol, glucagon and epinephrine) may result in hypoglycemia. These deficiencies are uncommon in patients without type 1 or advanced type 2 diabetes, and usually present with additional signs and/or symptoms (1). Since any condition that results in ACTH deficiency or directly interferes with cortisol secretion can cause hypoglycemia, primary and secondary adrenal insufficiency, for which simple treatment is available, should be considered. Adrenal insufficiency has multiple potential etiologies, including but not limited to autoimmune and infectious causes, as well as hemorrhage or infarction. An 8 AM cortisol level, with or without a simultaneous adrenocorticotropin (ACTH) level can be used as a screening test for adrenal insufficiency. Early morning cortisol values over 18 mcg/dL predict a normal response to ACTH stimulation and further testing for adrenal insufficiency is not needed. Cortisol values below 5 mcg/dL are suggestive of adrenal insufficiency. Cortisol values that are intermediate warrant further testing with ACTH stimulation (20-21). ACTH stimulation testing with either standard (250 mcg) or low dose (1 mcg) synthetic ACTH (cosyntropin) should be done unless the basal cortisol level has ruled out adrenal insufficiency. Serum cortisol concentrations should rise to ≥ 18 mcg/dL after either 30 or 60 minutes following the standard 250 mcg dose, and after 20 or 30 minutes following the low 1 mcg dose. Most patients can be evaluated by the standard 250 mcg ACTH stimulation test; however, the 1 mcg stimulation test may be preferable in patients with recent onset of suspected ACTH deficiency (21-22). Hypoglycemia associated with cortisol or growth hormone deficiency may present after a prolonged fast.

Critical illness, including sepsis and organ failure is a common setting for hypoglycemia. Dysglycemia in the setting of sepsis is common and thought to be initiated by activation of proinflammatory mediators and counter-regulatory hormones (23-27). Hyperglycemia results from increased hepatic gluconeogenesis and insulin resistance which exceeds the increase in glucose uptake by peripheral tissue and macrophage rich organs (liver, lung and spleen). Hypoglycemia is also common in critically ill patients with sepsis. Although this is usually related to insulin therapy, hypoglycemia can occur in the absence of insulin treatment and is associated with illness severity and mortality. Hypoglycemia that occurs in sepsis in the absence of exogenous insulin use is related to increases in glucose utilization which exceed production (26-27). Risk is higher with poor nutritional status including inadequate oral intake and in those requiring hemodialysis.

Hypoglycemia related to hepatic disease is primarily observed in the setting of massive and rapid hepatic destruction. Hypoglycemia can occur with viral hepatitis (28), but is atypical in other forms of liver disease. Hypoglycemia in acute liver failure is due to both impaired gluconeogenesis and depletion of hepatic glycogen stores and is associated with an increased risk of mortality. Glycogen storage diseases, which are caused by abnormalities in the enzymatic processes of glycogen storage or breakdown, are rare inherited diseases which may result in hypoglycemia. These represent a diverse group of illnesses which can present at varying ages from neonate to adult, and have distinct characteristics and treatments (29-31).

Hypoglycemia is common in patients with renal failure and can be seen in those with and without diabetes (32-33). The etiology of hypoglycemia in renal failure is multifactorial with decreased renal gluconeogenesis, decreased caloric intake, decreased renal clearance of insulin, and decreased metabolism of other medications that can cause hypoglycemia. Concurrent hepatic disease or sepsis are all possible contributing factors (24, 33-35). Insulin sensitivity may improve in uremic patients after starting renal replacement therapy, and this can contribute to an increased risk for hypoglycemia (36). In patients receiving hemodialysis, hypoglycemia is reduced with the addition of glucose to dialysis solutions (37).

Severe cardiac failure is sometimes accompanied by hypoglycemia. The pathogenesis of this is not well understood. Inhibited gluconeogenesis due to hepatic congestion as well as decreased glycogen stores from inadequate nutritional intake and reduced gastrointestinal absorption are proposed mechanisms (38-40).

Alcohol causes hypoglycemia primarily by inhibiting gluconeogenesis. Hypoglycemia can occur in individuals who drink alcohol in the setting of poor nutrition and depleted glycogen stores (1,23). Alcohol blunts the response of growth hormone to hypoglycemia (41). Alcohol can also increase the insulin response to a glucose load, which may result in postprandial hypoglycemia after eating a small meal (42). Alcohol-induced hypoglycemia is usually associated with elevated levels of β-hydroxybutyrate and low insulin and c-peptide levels.

Malnutrition, in the setting of body fat and muscle depletion, can also cause hypoglycemia due to limited substrates for gluconeogenesis and glycogenolysis (43-44). This has been observed in patients with eating disorders such as anorexia nervosa, mental health conditions, malabsorption, alcohol and substance use disorders and during starvation. Additional risk factors for malnutrition include homelessness, food insecurity, natural disasters, and child or elder abuse. After a prolonged period of poor caloric intake, the reintroduction of nutrients can cause a variety of metabolic and electrolyte disturbances. This is referred to as the Refeeding Syndrome, which is also sometimes associated with postprandial hypoglycemia (45-46).

Endogenous hyperinsulinism is a rare cause of hypoglycemia that can result from an insulinoma or pancreatic islet nesidioblastosis (1). Insulinomas primarily cause hypoglycemia in the fasting state, but may cause symptoms in the postprandial period as well. The incidence is 1/250,000 patient-years. Less than 10% are malignant, multiple or present in patients with the multiple endocrine neoplasia type 1 (MEN-1) syndrome (1). At the time of hypoglycemia, insulin, c-peptide and proinsulin levels are elevated and β-hydroxybutyrate levels are low (see Diagnostic Tests below).

Non-insulinoma pancreatogenous hypoglycemia typically causes hypoglycemia in the postprandial state. These patients have diffuse islet involvement with nesidioblastosis (islet hypertrophy, hyperplasia and enlarged and hyperchromatic β-cell nuclei) (47). Rarely, a genetic mutation causing hyperinsulinemia is diagnosed in adults, as was reported for a 20- year-old man with hyperinsulinemic hypoglycemia found to have a mutation in the ABCC8 gene affecting insulin secretion (48).

Hypoglycemia in patients with non-islet cell tumors is associated with high circulating levels of pro-IGF-II, also called “big” IGF-II (49). Overproduction of IGF-1 (50) as well as glucagon-like peptide 1 (GLP1) and somatostatin have also been reported (51-53). Hypoglycemia has been described in a variety of tumors but particularly in tumors of mesenchymal origin which are typically large and clinically apparent. Pro-IGF-II binds poorly to its binding proteins, enters tissue spaces and causes hypoglycemia due to its insulin-like actions. Growth hormone secretion is suppressed with resulting low IGF-1 levels, and pro IGFII to IGF II and IGF-II to IGF-I ratios are elevated (49-51). Endogenous insulin secretion is appropriately suppressed (1). There can be increased glucose utilization by the tumors as well.

Some patients who have had bariatric surgery for the treatment of obesity, most commonly Roux-en-Y gastric bypass surgery, will develop hypoglycemia. In one study, the incidence of hypoglycemia was 9.1% and 7.9% at 12 months and 60 months respectively after Roux-en-Y gastric bypass surgery (54). Inappropriate high post-prandial insulin and GLP-1 levels and alterations in glucagon levels as well as in GI function have been described (55-56). In a small study, use of a GLP-1 receptor antagonist decreased postprandial insulin secretion, correcting hypoglycemia (57).

Hypoglycemia may be “reactive”, related to the abnormal transport of food to the small intestine (56, 58-60). Children who have had a Nissen fundoplication with percutaneous endoscopic gastrostomy (PEG) tube can develop hypoglycemia related to the development of the dumping syndrome.

The insulin autoimmune syndrome or Hirata’s disease is characterized by the presence of antibodies to insulin and/or proinsulin or the insulin receptor (1,12, 62, 63). Antibodies to native insulin occur primarily in patients of Japanese and Korean descent, but have been reported in Caucasians as well. Exposure to sulfhydryl containing drugs such as clopidogrel or α-lipoic acid which also contains sulfur can cause the insulin autoimmune syndrome. It is hypothesized that the sulfhydryl group disrupts the insulin disulfide bond, increasing its immunogenicity (64). Late postprandial hypoglycemia occurs as insulin secreted in response to the meal disassociates from antibodies (1). The antibodies found in the insulin autoimmune syndrome can interfere with immunoassays of pancreatic hormones (63). The diagnosis is made with documentation of elevated insulin antibody levels in the absence of exposure to exogenous insulin, or elevated insulin receptor antibody levels. These patients may have other autoimmune diseases as well. Rarely, mutations in the insulin receptor gene cause hypoglycemia.

DIAGNOSTIC TESTS

Clinical practice guidelines for the evaluation and management of adult hypoglycemic disorders were published by the Endocrine Society in 2009 (1). The testing approach is also discussed in the Endotext chapter on pancreatic islet function testing (65).

TREATMENT

Immediate treatment should be focused on reversing the hypoglycemia. If the patient is able to ingest carbohydrates 15 to 20 grams of glucose should be given every 15 minutes until the hypoglycemia has resolved. If the patient is unable to ingest carbohydrates, or if the hypoglycemic episode is severe, parenteral glucose should be administered. In a healthcare setting intravenous dextrose is used. Twenty-five gram boluses of 50% dextrose are given until the hypoglycemia has resolved. If needed, an infusion of 10% or 20% dextrose can be used to sustain euglycemia in patients with recurrent episodes of hypoglycemia. In the outpatient setting, glucagon, given intranasal or as a subcutaneous or intramuscular injection, is used to correct hypoglycemia. Glucose gel and other forms of oral glucose should be used in impaired patients with caution and only in circumstances where no alternative is available, as they pose an aspiration risk.

Long-term treatment should be tailored to the specific hypoglycemic disorder, considering the burden of hypoglycemia on well-being and patient preferences. Offending medications should be discontinued and underlying illnesses treated, whenever possible.

HYPOGLYCEMIA IN NEONATES AND INFANTS

The presence of hypoglycemia in neonates and infants may be transient, especially during the first 2-3 days of life (Table 6). This is generally observed in newborns with prematurity, perinatal stress and/or a history of maternal diabetes. The Pediatric Endocrine Society (101) recommends focusing on treating hypoglycemia during the first 48 hours of life, and initiating a more complete diagnostic evaluation if hypoglycemia persists. The glucose threshold for evaluating hypoglycemia in this age group is controversial, with recommendations including <60 mg/dL (3.3 mmol/L) and <47 mg/dL (2.6 mmol/L). Whipple’s triad is of limited use in infants since they cannot communicate hypoglycemia. In neonates and infants, signs and symptoms of hypoglycemia can include lethargy, irritability, poor feeding, seizures or myoclonic jerks, respiratory distress, hypotonia, sweating and hypothermia.

Causes of hypoglycemia in the newborn period are listed in Table 6 and reviewed in more detail in references 31, 101-103. For the evaluation of hypoglycemia in this age group, particular attention is directed towards family history, congenital syndromes, genetic defects, and hormonal deficiencies. In addition to the evaluation recommended for adults (physical exam, liver, thyroid and renal function, pituitary/adrenal evaluation as indicated, simultaneous measurements of plasma glucose, insulin, c-peptide, proinsulin, and β-hydroxybutyrate, screen for oral hypoglycemic drugs, and glucagon stimulation; Table 4), measures of bicarbonate, free fatty acids, ammonia, lactate, total and free carnitine and acyl carnitine profile, plasma amino acids, IGFBP-1, urine for reducing substance and organic acids should be considered.

When hyperinsulinemic hypoglycemia is suspected, a carefully supervised fast can be conducted, with laboratory testing performed when the plasma glucose level is <50 mg/dL (2.8 mmol/L), followed by a glucagon challenge with measurements of the glucose response. Genetic mutation analysis when available is indicated in specific cases (e.g. to confirm a diagnosis, for genetic counseling and prenatal testing). Treatments are dependent upon the etiology of the hypoglycemia. Treatment options are discussed in the guidelines by the Pediatric Endocrine Society (101).

GUIDELINES

1. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ. Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94:709–728. [PubMed: 19088155]
2. Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, Levitsky LL, Murad MH, Rozance PJ, Simmons RA, Sterling MA, Weinstein DA, White NH, Wolfsdorf JI. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants and Children. J Pediatr. 2015;167:238–245. [PubMed: 25957977]
3. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101:364–89. [PMC free article: PMC4880116] [PubMed: 26760044]

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