What are the causes of anion gap metabolic acidosis?

Causes of Anion Gap Metabolic Acidosis

The main causes of anion gap metabolic acidosis include diabetic ketoacidosis, alcoholic ketoacidosis, lactic acidosis, toxic ingestions (methanol, ethylene glycol, salicylates), and uremia. 1, 2

Understanding Anion Gap

The anion gap is calculated as:

• Anion Gap = [Na+] - ([Cl-] + [HCO3-])
• Normal range: 8-12 mEq/L
• Elevated: >12 mEq/L

An elevated anion gap indicates the presence of unmeasured anions in the blood, which is a hallmark of certain types of metabolic acidosis 2.

Major Categories of Anion Gap Metabolic Acidosis

1. Ketoacidosis

• Diabetic Ketoacidosis (DKA)

  • Precipitating factors: infection, cerebrovascular accident, myocardial infarction, trauma, inadequate insulin, newly diagnosed type 1 diabetes 1
  • Laboratory findings: hyperglycemia, ketonemia, ketonuria

• Alcoholic Ketoacidosis (AKA)

  • Distinguished by clinical history
  • Plasma glucose ranges from mildly elevated to hypoglycemia (rarely >250 mg/dL)
  • Serum bicarbonate usually not lower than 18 mEq/L 1

• Starvation Ketosis

  • Less severe than DKA or AKA
  • Serum bicarbonate usually not lower than 18 mEq/L 1

2. Lactic Acidosis

• Type A (Hypoxic)

  • Caused by decreased oxygen delivery or tissue hypoperfusion
  • Associated with high mortality 3
  • Etiologies: shock, severe hypoxemia, carbon monoxide poisoning

• Type B (Non-hypoxic)

  • Drug-induced: biguanides (metformin)
  • Liver disease
  • Malignancy
  • Seizures

3. Toxic Ingestions

• Methanol

  • Metabolized to formic acid
  • Associated with severe acidosis and elevated osmolar gap
  • Treatment: alcohol infusion and dialysis 3

• Ethylene Glycol

  • Metabolized to glycolic acid and oxalic acid
  • Severe acidosis with elevated osmolar gap
  • Anion gap >27 mmol/L indicates need for extracorporeal treatment 1
  • Treatment: fomepizole or ethanol and hemodialysis 1

• Salicylates

  • Usually presents with mixed respiratory alkalosis and mild metabolic acidosis
  • Can cause increased anion gap 3

• Other Toxins

  • Paraldehyde
  • Toluene (can cause both high and normal anion gap acidosis)
  • Propylene glycol
  • Diethylene glycol 4, 5

4. Uremia

• Caused by decreased renal function and retention of unmeasured anions
• Usually a mild acidosis with moderate anion gap elevation 3
• Associated with decreased ammonia secretion 3

5. Less Common Causes

• 5-Oxoproline (Pyroglutamic) Acidosis

  • Associated with chronic paracetamol (acetaminophen) use
  • Risk factors: female gender, sepsis, impaired renal function, uncontrolled diabetes 6

• D-Lactic Acidosis

  • Seen in patients with short bowel syndrome or after gastric bypass surgery
  • Caused by bacterial fermentation in the gut 6

Diagnostic Approach

1. Calculate the anion gap and confirm metabolic acidosis with arterial blood gases
2. Evaluate for common causes using targeted laboratory tests:
   • Glucose, ketones (DKA)
   • Lactate (lactic acidosis)
   • BUN/creatinine (uremia)
   • Toxicology screen (toxic ingestions)
3. Consider osmolal gap for suspected toxic alcohol ingestion
   • Osmolal gap = measured osmolality - calculated osmolarity
   • Elevated osmolal gap (>10 mOsm/kg) suggests presence of unmeasured osmotically active substances 5
4. Correct anion gap for albumin when hypoalbuminemia is present 7
   • For every 1 g/dL decrease in albumin, add 2.5 mEq/L to the calculated anion gap

Clinical Pearls

• Multiple causes of anion gap metabolic acidosis can coexist in the same patient 6
• The relationship between changes in anion gap and serum bicarbonate can help identify mixed acid-base disorders 7
• Normal anion gap does not exclude the presence of organic acidosis, especially in patients with hypoalbuminemia 7
• An anion gap >27 mmol/L in ethylene glycol poisoning strongly indicates the need for extracorporeal treatment 1

By systematically evaluating patients with anion gap metabolic acidosis and understanding the various etiologies, clinicians can provide appropriate and timely interventions to address the underlying causes and prevent complications.