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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretagogue use
• High doses of beta-blockers
• Prolonged fasting/ malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries
• Chronic heavy alcohol use
• Sepsis
• Burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns
• Strenuous exercise in diabetic patients
• CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin, glucagon, and the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System. As the serum glucose level falls, several regulatory and counterregulatory mechanisms are induced. 

• Approximately 80 mg/dL: insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion decreased
• Approximately 68 mg/dL: glucagon, norepinephrine, and epinephrine secreted
  • Glucagon stimulates glycogenolysis and gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis
    • Pancreatic islets: decreases insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion and increases glucagon secretion
    • Muscle: decreases glucose uptake and increases glycogenolysis
    • Adipose: increases lipolysis, which provides glycerol for gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis
• Approximately 58–66 mg/dL: Growth hormone and cortisol are secreted, which have several roles:
  • Adipose: increase lipolysis
  • Liver: increase ketogenesis and gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. 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 Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane and increases cell sensitivity to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin, while insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion decreases.
  • Insulin-dependent diabetics do not have functional regulatory mechanisms; thus, serum insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin levels remain high.
• CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease:
  • Insulin is both cleared and metabolized by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys.
  • A GFR < 20 mL/min (as in CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease stage IV and end-stage renal disease) impairs these pathways, increasing the circulating serum level of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin.

In any patient, including diabetics:

• Insulin or insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretagogue use:
  • Most common cause of hypoglycemia
  • Insulin increases glucose uptake by skeletal muscle and adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue by up-regulating GLUT4 translocation.
  • Insulin secretagogues (sulfonylureas, meglitinides) stimulate endogenous insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries:
  • Prolonged decrease in glucose intake
  • Glycogenolysis, lipolysis, and gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis pathways are exhausted.
• Chronic heavy alcohol abuse:
  • Ethanol metabolism Ethanol metabolism Ethanol is a chemical compound that is produced in small amounts within the small intestine and is also ingested from alcoholic drinks. Ethanol's digestion involves a complex catabolic pathway that mainly takes place in the liver. Ethanol is turned into acetaldehyde, then to acetate, and finally into acetyl-CoA. Ethanol Metabolism produces nicotinamide adenine dinucleotide (NADH) as a by-product.
  • Elevated NADH levels reverse the gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin and C-peptide in an unregulated manner
  • Pancreatic non–islet cell tumor: produces insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin-like growth factor-2 (IGF-2), an insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. 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

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 Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of 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 Imaging of the brain Today, CT and MRI, especially the latter, are the preferred imaging methods for the study of the cranial vault and its contents. In conditions where emergent management is decided on the basis of presentation and imaging, CT has the advantage of rapid scan time and wider availability. Imaging of the Head and Brain. Management depends on the type of stroke and may include thrombolytics Thrombolytics Thrombolytics, also known as fibrinolytics, include recombinant tissue plasminogen activator (TPa) (i.e., alteplase, reteplase, and tenecteplase), urokinase, and streptokinase. The agents promote the breakdown of a blood clot by converting plasminogen to plasmin, which then degrades fibrin. Thrombolytics or neurosurgical intervention.
• Transient ischemic attack Transient ischemic attack Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA) ( TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. 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 Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. 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 Neurosurgery Neurosurgery is a specialized field focused on the surgical management of pathologies of the brain, spine, spinal cord, and peripheral nerves. General neurosurgery includes cases of trauma and emergencies. There are a number of specialized neurosurgical practices, including oncologic neurosurgery, spinal neurosurgery, and pediatric neurosurgery. 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 Thyrotoxicosis Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism, drug intoxication or withdrawal, hypoglycemia, hypoxia or hypercapnia, or infections such as encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis. Symptoms include delusions, auditory or visual hallucinations, and disorganized thought patterns. Management varies depending on the underlying cause.
• Sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs toxidrome: toxidrome resembling the neurogenic symptoms of hypoglycemia that is caused by certain drugs that stimulate the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System. Examples include stimulants Stimulants Stimulants are used by the general public to increase alertness and energy, decrease fatigue, and promote mental focus. Stimulants have medical uses for individuals with ADHD and sleep disorders, and are also used in combination with analgesics in pain management. 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 Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines.
• Major depression: mood disorder characterized by depressed mood/anhedonia. Major depression may include sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of 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.