Hypoglycemia

AUTHORS: Benjamin E. Hook, MD and Marcin Byra, DO

Definition

Hypoglycemia refers to abnormally low blood glucose levels in circulating plasma. It is defined as a glucose value <70 mg/dl (3.9 mmol/L). “Serious hypoglycemia” refers to values <54 mg/dl (3.0 mmol/L). “Severe hypoglycemia” is any glucose value necessitating external assistance to correct it. “Reactive hypoglycemia” refers to symptoms of hypoglycemia with plasma glucose value >70 mg/dl. A multitude of scenarios can lead to this potentially fatal condition.¹

Synonyms

Glycopenia

Low blood glucose

Low blood sugar

ICD-10CM CODES
E10.641		Type 1 diabetes mellitus with hypoglycemia with coma
E10.649		Type 1 diabetes mellitus with hypoglycemia without coma
E11.641		Type 2 diabetes mellitus with hypoglycemia with coma
E11.649		Type 2 diabetes mellitus with hypoglycemia without coma
E13.641		Other specified diabetes mellitus with hypoglycemia with coma
E13.649		Other specified diabetes mellitus with hypoglycemia without coma
E16.1		Other hypoglycemia
E16.2		Hypoglycemia, unspecified

Epidemiology & Demographics

Most commonly seen in patients with diabetes mellitus (DM)¹^,²
More common in type 1 DM. Estimated that glucose levels may be as low as 50 to 60 mg/dl ∼10% of the time in type 1 DM.¹^,³
Although less prevalent than type 1, absolute cases of hypoglycemia is higher in patients with type 2 DM because of the significantly larger population of people with type 2 DM. Rates of severe hypoglycemic episodes in type 1 DM range from 115 to 320 episodes/100 patient years, whereas rates for type 2 DM range from 35 to 70 episodes/100 patient years.²^,³
Elderly adults with DM are at higher risk of hypoglycemia because of alterations in adaptive physiologic responses to low glucose levels. In addition, this patient population has comorbidities, including cognitive and functional decline, that interfere with rapid identification and response to hypoglycemic episodes. Elderly patients are more likely to be hospitalized for insulin-related hypoglycemia than younger cohorts.²

Physical Findings & Clinical Presentation ¹

Symptoms are often nonspecific.
Early symptoms include sweating, pallor, anxiety, palpitations, hunger, and tremor.
Late symptoms with lower plasma glucose levels include seizures, altered mental status, and coma.
Profound or prolonged hypoglycemic episodes can cause irreversible brain injury, cardiopulmonary arrest, and death.
Older adults may present with atypical symptoms: Nausea, unsteadiness, falls, or transient ischemia that can delay diagnosis.²

Etiology (Box 1

Systemic glucose balance and effects of circulating hormones on endogenous production and use of glucose are described in Table 1. Physiologic responses to decreasing plasma glucose concentrations are summarized in Table 2.
Medications are the most common cause of hypoglycemia.¹^,²
Most common causes include hyperinsulinemia due to therapeutic treatment with exogenous insulin and/or insulin secretagogues (sulfonylureas [SU] and meglitinides [MG]). Can also be exacerbated by medication use without proper exogenous glucose intake or increased insulin sensitivity due to weight loss.²
Alcohol use leading to lack of endogenous glucose production ¹^,²
Critical illness
1. Organ failure (hepatic, cardiac, or renal)
2. Sepsis (urinary tract infection and pneumonia common sources in elderly population)
Hormone deficiency (cortisol, glucagon, and epinephrine)
Endogenous hyperinsulinism (insulinoma, functional β-cell disorders, insulin autoimmune hypoglycemia)
Rare fatal episodes thought to be secondary to ventricular arrhythmias

TABLE 1 Systemic Glucose Balance ^a and Effects of Circulating Hormones on Endogenous Production and Use of Glucose

Source of Glucose Influx or Efflux	Hormonal Effects
Source of Glucose Influx or Efflux	Insulin	Glucagon	Epinephrine
Glucose Influx into the Circulation
Exogenous glucose delivery
Endogenous glucose delivery
In liver: Glycogenolysis and gluconeogenesis	↓	↑	↑
In kidneys: Gluconeogenesis	↓		↑
Glucose Efflux Out of the Circulation
Ongoing brain glucose utilization
Variable glucose utilization by other tissues (e.g., muscle fat, liver, kidneys)	↑		↓

^aTotal glucose influx = total glucose efflux.

From Melmed S et al: Williams textbook of endocrinology, ed 14, Philadelphia, 2019, Elsevier.

TABLE 2 Physiologic Responses to Decreasing Plasma Glucose Concentrations

Response	Glycemic Threshold ^a (mmol/L [mg/dl])	Physiologic Effects	Role in Prevention or Correction of Hypoglycemia (Glucose Counterregulation)
↓Insulin	4.4-4.7 (80-85)	↑R_a (↓ R_d)	Primary glucose regulatory factor, first defense against hypoglycemia
↑Glucagon	3.6-3.9 (65-70)	↑R_a	Primary glucose counterregulatory factor, second defense against hypoglycemia
↑Epinephrine	3.6-3.9 (65-70)	↑R_a, ↓ R_c	Involved, critical when glucagon is deficient, third defense against hypoglycemia
↑Cortisol and growth hormone	3.6-3.9 (65-70)	↑R_a, ↓ R_c	Involved, not critical
Symptoms	2.8-3.1 (50-55)	↑Exogenous glucose	Prompt behavioral defense (food ingestion)
↓Cognition	<2.8 (50)	-	(Compromises behavioral defense)
↓Brain glucose metabolism	<2.8 (50)	-	-

R_a, Rate of glucose appearance, glucose production by the liver and kidneys; R_c, rate of glucose clearance by insulin-sensitive tissues; R_d, rate of glucose disappearance, glucose utilization by insulin-sensitive tissues such as skeletal muscle (no direct effect on central nervous system glucose utilization).

^aArterialized venous, not venous, plasma glucose concentrations.

From Melmed S et al: Williams textbook of endocrinology, ed 14, Philadelphia, 2019, Elsevier.

BOX 1 Causes of Hypoglycemia

Postprandial Hypoglycemia (Reactive)

Postoperative rapid gastric emptying (alimentary hyperinsulinism)
Fructose intolerance
Galactosemia
Leucine intolerance
Idiopathic

Fasting Hypoglycemia

Overuse of glucose
Elevated insulin levels
Exogenous insulin (therapeutic, factitious)
Oral hypoglycemic (therapeutic, factitious)
Islet cell disorders (adenoma, nesidioblastosis, cancer)
Excessive islet cell function (prediabetes, obesity)
Antibodies to endogenous insulin
Normal to low insulin levels
Ketotic hypoglycemia
Hypermetabolic state (sepsis)
Rare extrapancreatic tumors
Carnitine deficiency

Underproduction of Glucose

Hormone deficiencies (growth hormone, glucagon, hypoadrenalism)
Enzyme disorders
Glycogen metabolism (glycogen phosphorylase, glycogen synthetase)
Hexose metabolism (glucose-6-phosphatase, fructose-1,6-biphosphatase)
Glycolysis, Krebs cycle (phosphoenolpyruvate carboxykinase, pyruvate carboxylase, malate dehydrogenase)
Alcohol and probably other drugs
Liver disease (cirrhosis, fulminant hepatic failure)
Severe malnutrition

From Jankovic J et al: Bradley and Daroff’s neurology in clinical practice, ed 8, Philadelphia, 2022, Elsevier.

Diagnosis ¹

Characterized by Whipple triad:

Symptoms potentially explained by hypoglycemia
Low blood glucose levels during the symptoms
Relief of symptoms with administration of glucose or glucagon

Treatment ⬆ ⬇

Nonpharmacologic Therapy ¹

Recognition of signs and symptoms, and self-monitoring of blood glucose, are especially important in insulin-deficient patients.
Avoiding drugs that can exacerbate condition (e.g., alcohol) if it occurs on repeated occasions.
Bedtime snacks if hypoglycemia occurs at night.
In situations caused by tumor etiologies (e.g., islet cell, insulinoma, and nonislet cell), definitive treatment may require surgical removal.

Pharmacologic Therapy ¹ ⁴

Treating the underlying etiology that exacerbates hypoglycemia (e.g., infection, proper diabetic regimen, proper diabetic diet)
Fast-acting carbohydrates (e.g., glucose tablets, hard candy, intravenous [IV] dextrose infusion)
Pure glucose (dextrose) if caused by insulin secretagogue in addition with α-glucosidase inhibitor
In severe hypoglycemia with seizure activity, 25 g of 50% dextrose IV or 0.5 to 1.0 mg intramuscular/subcutaneous glucagon
In persistent hypoglycemia after IV dextrose, therapy think sulfonylurea overdose or insulin pump malfunction. If an insulin pump is present, remove it. If sulfonylurea overdose is suspected, treat with IV dextrose infusion and octreotide 50 to 100 μg every 6 to 12 h for adults and 1 to 2 μg/kg every 6 to 12 h.⁴
Fig. 2 describes a management algorithm for hypoglycemia

Figure 2 Management of hypoglycemia.

IV, Intravenous; SC, subcutaneous.

From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

Referral

Most scenarios of hypoglycemia can be managed by primary care physicians by adjusting medications.
If the cause is not clear, then endocrinology referral is recommended.
Severe symptomatic hypoglycemia needs emergent treatment.

Pearls & Considerations ⬆ ⬇

Hypoglycemia can cause severe morbidity and death if not dealt with promptly and effectively.
Hypoglycemia is very common in patients with DM, especially type 1 DM, and most commonly it is a side effect of medications.
Elderly patients with DM are at higher risk for serious hypoglycemic episodes and can initially present with atypical symptoms.
In patients who are hospitalized, the etiology is often multifactorial.
Clinically important hypoglycemia is uncommon in nondiabetic patients, and evaluation for a hypoglycemic disorder in these patients should only occur if the Whipple triad is met.
Pediatric hypoglycemia: A classification of hypoglycemia in infants and children is summarized in Table E3.

TABLE E3 Classification of Hypoglycemia in Infants and Children

NEONATAL TRANSITIONAL (ADAPTIVE) HYPOGLYCEMIA
Associated With Inadequate Substrate or Immature Enzyme Function in Otherwise Normal Neonates Prematurity Small for gestational age Normal newborn Transient Neonatal Hyperinsulinism Infant of diabetic mother Small for gestational age Discordant twin Birth asphyxia Infant of toxemic mother
NEONATAL, INFANTILE, OR CHILDHOOD PERSISTENT HYPOGLYCEMIA
Hyperinsulinism Recessive K_ATP channel HI Recessive HADH (hydroxyl acyl-CoA dehydrogenase) mutation HI Recessive UCP2 (mitochondrial uncoupling protein 2) mutation Hl Focal K_ATP channel HI Dominant K_ATP channel HI Atypical congenital hyperinsulinemia (no mutations in ABCC8 or KCN11 genes) Dominant glucokinase HI Dominant glutamate dehydrogenase HI (hyperinsulinism-hyperammonemia syndrome) Dominant mutations in HNF-4A and HNF-1A (hepatocyte nuclear factors 4α and 1α) HI with monogenic diabetes of youth later in life Dominant mutation in SLC16A1 (the pyruvate transporter)-exercise-induced hypoglycemia Activating mutations in the calcium channel CACNA1D (permit calcium influx and thus unregulated insulin secretion) Acquired or familial islet adenoma associated with mutations in MEN1 gene Beckwith-Wiedemann syndrome Kabuki syndrome Insulin administration (Munchausen syndrome by proxy) Oral sulfonylurea drugs Congenital disorders of glycosylation Counter-Regulatory Hormone Deficiency Panhypopituitarism Isolated growth hormone deficiency Adrenocorticotropic hormone deficiency Addison disease (including congenital adrenal hypoplasia, adrenal leukodystrophy, triple A syndrome, ACTH receptor deficiency, and autoimmune disease complex) Epinephrine deficiency Glycogenolysis and Gluconeogenesis Disorders Glucose-6-phosphatase deficiency (GSD la) Glucose-6-phosphate translocase deficiency (GSD lb) Amylo-1,6-glucosidase (debranching enzyme) deficiency (GSD III) Liver phosphorylase deficiency (GSD VI) Phosphorylase kinase deficiency (GSD IX) Glycogen synthetase deficiency (GSD 0) Fructose-1,6-diphosphatase deficiency Pyruvate carboxylase deficiency Galactosemia Hereditary fructose intolerance Lipolysis Disorders Fatty Acid Oxidation Disorders Carnitine transporter deficiency (primary carnitine deficiency) Carnitine palmitoyltransferase-1 deficiency Carnitine translocase deficiency Carnitine palmitoyltransferase-2 deficiency Secondary carnitine deficiencies Very-long-, long-, medium-, short-chain acyl-CoA dehydrogenase deficiency
OTHER ETIOLOGIES
Substrate-Limited Causes Ketotic hypoglycemia Poisoning-drugs Salicylates Alcohol Oral hypoglycemic agents Insulin Propranolol Pentamidine Quinine Disopyramide Ackee fruit (unripe)-hypoglycin Litchi-associated toxin (toxin hypoglycemic syndrome) Vacor (rat poison) Trimethoprim-sulfamethoxazole (with renal failure) L-Asparaginase and other antileukemic drugs Liver Disease Reye syndrome Hepatitis Cirrhosis Hepatoma
AMINO ACID AND ORGANIC ACID DISORDERS
Maple syrup urine disease Propionic academia Methylmalonic academia Tyrosinosis Glutaric aciduria 3-hydroxy-3-methylglutaric aciduria
SYSTEMIC DISORDERS
Sepsis Carcinoma/sarcoma (secreting-insulin-like growth factor II) Heart failure Malnutrition Malabsorption Antiinsulin receptor antibodies Antiinsulin antibodies Neonatal hyperviscosity Renal failure Diarrhea Burns Shock Chiari malformation Postsurgical complication Pseudohypoglycemia (leukocytosis, polycythemia) Excessive insulin therapy of insulin-dependent diabetes mellitus Factitious disorder Nissen fundoplication (dumping syndrome) Falciparum malaria

GSD, Glycogen storage disease; HI, hyperinsulinemia; KATP, regulated potassium channel.

From Kliegman RM, St Geme J, eds: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

Related Content

Diabetes Mellitus (Related Key Topic)

Insulinoma (Related Key Topic)

Differential Diagnosis

Hypoglycemic symptoms in the presence of normal plasma glucose levels (>70 mg/dl) point to other etiologies: Postprandial syndrome, stroke, sepsis, seizure/postictal state, cardiac disease, psychiatric disease, metabolic disorders (hyperthyroidism, pheochromocytoma), drug intoxication.¹

Workup

If Whipple triad is positive, the next step is to consider a patient’s medical status.¹
Iatrogenic factors are the most common causes of hypoglycemia in hospitalized patients (review the NPO status, timing of feeding, glucose-lowering medications, and interactions between medications).¹
Detailed history, including past medical history, a thorough medication history, and timing of hypoglycemia (in regard to meals and medications).
Special attention should be given to chronic diseases that can precipitate hypoglycemia such as chronic renal disease with a glomerular filtration rate <60.²

Laboratory Tests

An algorithm for recognition and evaluation of hypoglycemia is described in Fig. E1.
If the cause is not apparent after a thorough history, the following is appropriate:

Figure E1 Recognition and evaluation of hypoglycemia.

From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

Fasting

If symptoms witnessed when fasting, with verified low blood glucose levels, consider the following laboratory tests: Plasma glucose, β-hydroxybutyrate (BHOB), insulin, C-peptide, proinsulin, screen for SU and MG metabolites.¹

Postprandial

Plasma glucose, insulin, C-peptide, and proinsulin before ingestion of the meal and every 30 min thereafter for 5 h.¹
Only evaluate the samples drawn when glucose levels are <60 mg/dl.
If a patient has a presentation consistent with Whipple triad, then measure SU, MG, and antibodies to insulin.¹

72-H Fast¹

Collect blood specimens for measurement of plasma glucose, insulin, C-peptide, proinsulin, and BHOB every 6 h until the glucose concentration is <60 mg/dl.
Increase frequency of sampling to every 1 to 2 h.
Insulin, C-peptide, and proinsulin are only relevant in those specimens in which the plasma glucose concentration is <60 mg/dl.
The fast should be ended when any of the following occurs:
1. The plasma glucose concentration is <45 mg/dl.
2. The patient has symptoms or signs of hypoglycemia.
3. 72 h has elapsed.
4. The plasma glucose concentration is <55, and Whipple triad has been documented on a prior occasion.
Insulin antibodies are also measured but do not need to be measured during the hypoglycemic state.

Imaging Studies¹

If hypoglycemia is suspected secondary to an insulinoma or malignancy, transabdominal ultrasound (US), computed tomography scan, or endoscopic US can be used to help with diagnosis as well as for staging purposes.

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Basic Information ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

Related Content ⬆