Hypoglycemia

Overview

Definition

Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L).

• Constitutes the lower limit of the physiologic fasting range in nondiabetic patients
• Constitutes the threshold for glucagon and epinephrine release
• In diabetic patients, hypoglycemia may be any abnormally low plasma glucose concentration (with or without symptoms) that exposes them to harm, since glycemic thresholds that trigger symptoms vary. 
• Serum glucose < 54 mg/dL (< 3 mmol/L) is clinically important hypoglycemia.
  • Should never be reached physiologically by nondiabetic patients
  • Requires immediate intervention because of acute and chronic sequelae for the patient

Classification

• Severe: requires medical intervention 
• Documented symptomatic: serum glucose ≤ 70 mg/dL + associated symptoms
• Asymptomatic: serum glucose ≤ 70 mg/dL without associated symptoms
• Probable symptomatic: hypoglycemic symptoms without a serum glucose measurement
• Pseudohypoglycemia: serum glucose > 70 mg/dL and associated symptoms in a diabetic patient

Etiology

• Insulin or insulin secretagogue use
• High doses of beta-blockers
• Prolonged fasting/malnutrition
• Chronic heavy alcohol use
• Sepsis
• Burns
• Strenuous exercise in diabetic patients
• CKD in diabetic patients

Pathophysiology

Glucose homeostasis

Serum glucose levels are maintained within the normal range of 71–99 mg/dL owing to a coordinated balance between insulin, glucagon, and the sympathetic nervous system. As the serum glucose level falls, several regulatory and counterregulatory mechanisms are induced. 

• Approximately 80 mg/dL: insulin secretion decreased
• Approximately 68 mg/dL: glucagon, norepinephrine, and epinephrine secreted
  • Glucagon stimulates glycogenolysis and gluconeogenesis in the liver.
  • Norepinephrine acts systemically to cause the adrenergic symptoms of hypoglycemia, including tachycardia and diaphoresis.
  • Epinephrine has multiple roles in multiple organs:
    • Liver: stimulates glycogenolysis and gluconeogenesis
    • Pancreatic islets: decreases insulin secretion and increases glucagon secretion
    • Muscle: decreases glucose uptake and increases glycogenolysis
    • Adipose: increases lipolysis, which provides glycerol for gluconeogenesis
• Approximately 58–66 mg/dL: Growth hormone and cortisol are secreted, which have several roles:
  • Adipose: increase lipolysis
  • Liver: increase ketogenesis and gluconeogenesis
  • Occurs over hours

Pathophysiology

Hypoglycemia can be caused by various conditions and medications.

In diabetic patients:

• Strenuous exercise:
  • Skeletal muscle contraction up-regulates glucose transporter 4 (GLUT4) translocation to the cell membrane and increases cell sensitivity to insulin, while insulin secretion decreases.
  • Insulin-dependent diabetics do not have functional regulatory mechanisms; thus, serum insulin levels remain high.
• CKD:
  • Insulin is both cleared and metabolized by the kidneys.
  • A GFR < 20 mL/min (as in CKD stage IV and end-stage renal disease) impairs these pathways, increasing the circulating serum level of insulin.

In any patient, including diabetics:

• Insulin or insulin secretagogue use:
  • Most common cause of hypoglycemia
  • Insulin increases glucose uptake by skeletal muscle and adipose tissue by up-regulating GLUT4 translocation.
  • Insulin secretagogues (sulfonylureas, meglitinides) stimulate endogenous insulin secretion.
  • May be iatrogenic or intentional (self-harm, factitious disorder)
• High doses of beta-blockers:
  • Competitively inhibit beta-adrenergic receptors  
  • Reduce the epinephrine counterregulatory response of hypoglycemia
  • Mask the adrenergic signs and symptoms of hypoglycemia
• Prolonged fasting/malnutrition:
  • Prolonged decrease in glucose intake
  • Glycogenolysis, lipolysis, and gluconeogenesis pathways are exhausted.
• Chronic heavy alcohol abuse:
  • Ethanol metabolism produces nicotinamide adenine dinucleotide (NADH) as a by-product.
  • Elevated NADH levels reverse the gluconeogenesis pathway, favoring lactate and malate production instead of glucose.
• Sepsis and burns:
  • Hypermetabolic states
  • Increased basal metabolic rate leads to increased glucose utilization and decreased counterregulation.
• Tumors:
  • Insulinoma: pancreatic islet neuroendocrine tumor producing insulin and C-peptide in an unregulated manner
  • Pancreatic non–islet cell tumor: produces insulin-like growth factor-2 (IGF-2), an insulin receptor agonist

Clinical Presentation

The clinical signs and symptoms of hypoglycemia can be characterized as 2 types:

• Neuroglycopenic (hypoglycemia in the brain)
• Neurogenic (autonomic)

Diabetic patients who exhibit these signs and symptoms do not necessarily require further workup. However, nondiabetic patients who exhibit the Whipple triad do require further workup to determine the etiology of a possible hypoglycemic disorder.

• Neuroglycopenic symptoms:
  • Confusion
  • Dizziness
  • Irritability
  • Weakness
  • Drowsiness
  • Seizure
  • Somnolence or coma
• Neurogenic symptoms:
  • Pallor
  • Tachycardia and palpitations
  • Tremor
  • Diaphoresis
  • Anxiety
  • Paresthesias
• Whipple triad: in nondiabetic patients
  • Confirmed glucose concentration ≤ 70 mg/dL (≤ 3.9 mmol/L)
  • Signs and symptoms associated with hypoglycemia (as above)
  • Resolution of symptoms after the management of hypoglycemia

Diagnosis

The diagnosis of hypoglycemia requires only a reliable means of measuring blood glucose. This testing includes hospital point-of-care testing or laboratory measurement and excludes home glucose monitors.

Further investigation into the etiology of hypoglycemia is reserved primarily for nondiabetic patients exhibiting the Whipple triad.

General approach

• Confirm hypoglycemic levels by reliable form of serum glucose measurement.
• Complete a thorough history and physical exam.
• Review the medications to rule out medication-induced hypoglycemia (e.g., insulin, insulin secretagogues, beta-blockers).
• Obtain laboratory and imaging studies as clinically indicated.
• Exclude heavy alcohol use, sepsis, and burns.
• Repeat the measurement in circumstances similar to those of the first occurrence (e.g., fasting or postprandial).

Laboratory studies

• Serum glucose: ≤ 70 mg/dL (≤ 3.9 mmol/L)
• Insulin, proinsulin, and C-peptide:
  • Pre-proinsulin is the molecule secreted by the beta islet cells of the pancreas This molecule is cleaved into proinsulin, which is then cleaved into insulin and C-peptide. 
  • Increased endogenous insulin production/secretion results in hyperinsulinemia with high proinsulin and C-peptide levels.
  • Hyperinsulinemia with high C-peptide levels can be caused by an insulinoma or an insulin secretagogue.
  • Exogenous insulin administration causes inhibition of endogenous insulin and C-peptide secretion.
• Beta-hydroxybutyrate:
  • A ketone produced during fatty acid metabolism in the absence of adequate serum glucose
  • Elevated levels are seen with prolonged fasting/starvation or when there is inadequate insulin secretion (e.g., in type 1 diabetes mellitus).
• Sulfonylurea and meglitinide urinary screening test:
  • Detects metabolites of these medications in urine
  • Used when there is clinical suspicion or if medication history is unreliable 
• Urinalysis and urine culture:
  • To rule out urinary tract infection as a cause of hypoglycemia
  • Common cause of occult infection, especially in the elderly
• Blood culture:
  • To rule out bacteremia as a cause of hypoglycemia
  • Used when there is clinical suspicion as well as in the presence of SIRS criteria
• CK-MB and troponins:
  • To rule out acute coronary syndrome as a cause of hypoglycemia
  • Paired with ECG

Imaging studies

• Chest X-ray: to rule out pneumonia as a cause of hypoglycemia
• CT or MRI of the abdomen and pelvis: to look for pancreatic or extrapancreatic insulinoma if clinically suspected

Management

The primary goal of management is to raise serum glucose as quickly and as safely as possible. The secondary goal may be to ensure maintenance of the serum glucose with continuous monitoring and frequent serum glucose measurements. Generally, the approach depends on the severity of symptoms.

Patients without altered mental status

• Oral fast-acting carbohydrates such as juice, candy, or glucose pills, if patient can follow directions and swallow (i.e., the gag reflex is intact)
• Glucose gel applied to the oral mucosa

Patients with altered mental status

• Primary interventions:
  • IV dextrose bolus
  • IV dextrose maintenance fluid
  • Regular monitoring of blood glucose
• Secondary interventions:
  • Magnesium and potassium replacement
  • IM glucagon
  • IV steroids

Differential Diagnosis

The following conditions may mimic the signs and symptoms of hypoglycemia. Conversely, whenever a below conditions is suspected, a serum glucose measurement should be performed to rule out hypoglycemia.

• Stroke: acute disruption in brain function secondary to ischemia. Stroke is usually caused by either a thromboembolic or a hemorrhagic event and is classified as either ischemic or hemorrhagic. Symptoms vary depending on the vascular territory of the brain affected but can include altered mental status, motor or sensory deficits, somnolence, and dizziness. Diagnosis is typically made with imaging of the brain. Management depends on the type of stroke and may include thrombolytics or neurosurgical intervention.
• Transient ischemic attack (TIA): transient disruption in brain function caused by ischemia without infarction. Whereas a stroke causes permanent loss of brain tissue, a transient ischemic attack results in no permanent damage to tissue, and symptoms typically resolve within 24 hours. Causes are similar to those for ischemic strokes: thrombosis, embolism, or hypoperfusion secondary to hypotension. Diagnosis is based on the clinical history and ruling out stroke with normal imaging findings. 
• Focal or generalized seizure: acute period of abnormal electrical activity in the brain. Seizure may involve 1 region (focal) or both hemispheres of the brain simultaneously (generalized). Signs and symptoms vary depending on the type of seizure and the areas of the brain involved but can include altered mental status, visual changes, and jerking movements. Causes include metabolic abnormalities, intracranial hemorrhage, hypoglycemia, and primary seizure disorders. 
• Traumatic brain injury: disruption in brain function as a result of an external force. Signs and symptoms of traumatic brain injury can range from transient confusion and headache to severe and permanent cognitive and physical disability. Diagnosis should be made using the advanced trauma life support approach and is aided by the history, symptoms, and imaging. Management depends on the severity and can range from rest with minimal external stimuli to intubation with respiratory and hemodynamic support.
• Brain tumor: abnormal growth within the brain that may be either benign or malignant. Brain tumors can cause persistent headaches as well as neurologic symptoms by mass effect depending on the brain region affected. Diagnosis is made by imaging. Management may involve radiation, chemotherapy, and/or neurosurgery.
• Psychosis: condition defined by an abnormal perception of reality. Psychosis may be a primary psychiatric condition or a secondary condition due to a metabolic abnormality such as thyrotoxicosis, drug intoxication or withdrawal, hypoglycemia, hypoxia or hypercapnia, or infections such as encephalitis. Symptoms include delusions, auditory or visual hallucinations, and disorganized thought patterns. Management varies depending on the underlying cause.
• Sympathomimetic toxidrome: toxidrome resembling the neurogenic symptoms of hypoglycemia that is caused by certain drugs that stimulate the sympathetic nervous system. Examples include stimulants such as cocaine or methamphetamine. Symptoms of sympathomimetic toxidrome can include tachycardia and palpitations, tremors, diaphoresis, and anxiety. Diagnosis can be clinical and is aided by drug screens, improvement in symptoms over time, and ruling out other disorders. Management for agitation involves benzodiazepines.
• Major depression: mood disorder characterized by depressed mood/anhedonia. Major depression may include sleep disturbances, feelings of guilt, low energy, poor concentration, poor appetite, psychomotor slowing, and suicidality. Decreased alertness and psychomotor activity may be present and may resemble other metabolic disorders. Diagnosis involves clinical history and ruling out organic etiologies. Management is with CBT and medication.