Hypoglycemia

Definition

1. Symptoms and/or signs compatible with hypoglycemia
2. A low measured plasma glucose concentration
3. Resolution of symptoms when glucose is raised

• Goldman-Cecil Medicine, Chapter 211

Pathophysiology

• Glucose input: intestinal absorption, glycogenolysis, gluconeogenesis (from lactate, pyruvate, alanine, glutamine, glycerol)
• Glucose utilization: insulin-dependent uptake by muscle, adipose tissue, and liver

1. Cessation of insulin release
2. Release of counter-regulatory hormones - glucagon (primary), epinephrine, cortisol, growth hormone - which stimulate hepatic glycogenolysis and gluconeogenesis

• Goldman-Cecil Medicine, p. 2490; Rosen's Emergency Medicine, p. 2547

Etiology / Differential Diagnosis

In Diabetic Patients (most common overall)

• Insulin therapy - most frequent cause; accounts for ~2-6% of deaths in type 1 DM
• Sulfonylureas - prolonged, severe hypoglycemia; particularly dangerous
• Precipitating factors: missed meals, increased exercise, recent weight loss, alcohol, renal failure (decreased drug clearance), lipohypertrophy at injection sites
• Metformin, thiazolidinediones, DPP-4 inhibitors, GLP-1 agonists rarely cause significant hypoglycemia alone (only if combined with insulin/sulfonylureas)

In Non-Diabetic Patients

Postprandial (reactive) hypoglycemia

• Alimentary hyperinsulinism - post-gastrectomy, gastrojejunostomy, pyloroplasty, vagotomy, Roux-en-Y gastric bypass (dumping syndrome)

Fasting hypoglycemia - Endogenous hyperinsulinism

• Insulinoma - most common cause of endogenous hyperinsulinemic hypoglycemia in adults
• Non-insulinoma pancreatogenous hypoglycemia
• Insulin autoimmune syndrome
• Insulin receptor mutations/antibodies

Hormone deficiencies

• ACTH deficiency (cortisol deficiency), growth hormone deficiency, glucagon deficiency, adrenal insufficiency

Drugs

• Beta-blockers, salicylates, alcohol (blocks gluconeogenesis), quinine, pentamidine, haloperidol, levofloxacin, gatifloxacin, disopyramide, indomethacin, methadone

Critical illness / Organ failure

• Severe hepatic disease (impaired glycogenolysis/gluconeogenesis)
• Renal failure (decreased insulin clearance, impaired gluconeogenesis)
• Sepsis, endotoxic shock

Tumors

• Non-islet cell tumors secreting IGF-2 ("IGF-2-oma")

Pediatric/Neonatal

• Congenital hyperinsulinism (ABCC8, KCNJ11, GCK, GDH, HADH mutations)
• Glycogen storage diseases (G6Pase deficiency, etc.)
• Fatty acid oxidation defects (MCAD, VLCAD)
• Organic acidemias, galactosemia, maple syrup urine disease, fructosemia
• Goldman-Cecil Medicine, Table 211-1

Clinical Features

1. Adrenergic/Autonomic symptoms (early - catecholamine release)

• Sweating, tremor, palpitations, tachycardia, anxiety, nervousness, pallor, hunger

2. Neuroglycopenic symptoms (later - brain glucose deprivation)

• Confusion, bizarre behavior, difficulty concentrating
• Headache, visual disturbances
• Focal neurological deficits
• Seizures
• Coma

Hypoglycemia unawareness: A dangerous complication (especially in long-standing type 1 DM) where adrenergic warning symptoms are absent, and the patient rapidly progresses to unarousable coma without prodrome. Caused by prior hypoglycemic exposure blunting the neurohumoral counter-regulatory response.

Somogyi phenomenon: Excessive insulin dosing causes unrecognized nocturnal hypoglycemia, triggering counter-regulatory rebound hyperglycemia by morning. Clinicians may mistakenly increase insulin, worsening the cycle.

• Rosen's Emergency Medicine, p. 2547-2548

Diagnosis

• Rosen's Emergency Medicine, p. 2548; Goldman-Cecil Medicine

Management

Mild to Moderate (Alert Patient)

• Oral glucose - 15-20 g fast-acting carbohydrates (glucose tablets, juice, regular soda), recheck in 15 minutes, repeat if still low
• Follow with a meal or snack to prevent recurrence

Severe (Altered Consciousness / Unable to Take Oral)

Note: Glucagon is ineffective in alcohol-induced hypoglycemia (depleted hepatic glycogen stores). Thiamine should be given alongside dextrose if alcohol use disorder is suspected (to prevent Wernicke encephalopathy).

Sulfonylurea-Induced Hypoglycemia (special case)

• Tends to be prolonged and severe
• Octreotide (somatostatin analog) 50-100 mcg IV or SC every 12 hours (adult); 0.1 mcg/kg in children - inhibits further insulin release
• Observe for minimum 24 hours given risk of delayed/recurrent hypoglycemia (especially in renal failure, children, after overdose)
• Rosen's Emergency Medicine, p. 2548-2549

Disposition

• Type 1 DM with brief, correctable episode - may discharge after a meal, with short-term follow-up and identification/correction of precipitant
• Sulfonylurea-induced - admit if recurrent hypoglycemia in the ED
• Unknown cause / persistent / severe - admit for monitoring and workup
• Nondiabetic patients - workup for insulinoma or other causes based on clinical context

Risk Factors for Hypoglycemia in Diabetes

Key Points to Remember

• The Whipple triad remains the clinical standard for confirming hypoglycemia
• In type 1 DM, counter-regulation fails progressively - glucagon loss occurs early, then epinephrine
• Hypoglycemia unawareness greatly increases the risk of severe events
• Alcohol blocks gluconeogenesis - glucagon will not work in this setting
• Sulfonylureas cause prolonged hypoglycemia; octreotide and extended observation are required
• In children and neonates, consider congenital causes and use D10W or D25W (not D50W) to avoid rebound hyperglycemia