What is the etiology of metabolic acidosis with an elevated anion gap?

Etiology of Elevated Anion Gap Metabolic Acidosis

The etiology of elevated anion gap metabolic acidosis can be categorized into four main groups: lactic acidosis, ketoacidosis, toxin/drug-induced acidosis, and uremia. 1

Definition and Diagnosis

Metabolic acidosis is defined as a blood pH below 7.35, corresponding to a hydrogen ion concentration greater than 45 nmol/L. An elevated anion gap (>12 mEq/L) indicates the presence of unmeasured anions in the blood. 2

Major Causes of Elevated Anion Gap Metabolic Acidosis

1. Lactic Acidosis

• Results from decreased oxygen delivery or defective oxygen utilization
• Associated with high mortality
• Common in shock states, tissue hypoperfusion, or severe hypoxemia 1

2. Ketoacidosis

• Diabetic ketoacidosis (DKA): Insulin deficiency leading to increased lipolysis and ketone body formation
• Alcoholic ketoacidosis: Occurs in chronic alcoholics with recent binge drinking followed by reduced food intake
• Starvation ketoacidosis: Prolonged fasting leading to ketone production 1

3. Toxin/Drug-Induced Acidosis

• Methanol: Metabolized to formic acid
• Ethylene glycol: Metabolized to glycolic acid and oxalic acid
• Salicylates: Causes mixed respiratory alkalosis and metabolic acidosis
• Acetaminophen overuse: Can lead to 5-oxoprolinemia (pyroglutamic acidosis), especially with chronic use and poor nutrition 3, 4
• Propylene glycol: Found in some IV medications
• Isoniazid: Can cause lactic acidosis 1, 4

4. Uremia (Renal Failure)

• Decreased ammonia secretion and retention of unmeasured anions
• Usually associated with a mild anion gap acidosis
• One of the most common causes of high anion gap acidosis 1, 5

5. Other Causes

• Severe hyperphosphatemia: Can contribute to anion gap acidosis 5
• Inborn errors of metabolism: Various genetic disorders affecting metabolic pathways

Clinical Approach to Diagnosis

1. Laboratory Assessment:

   • Arterial blood gases
   • Complete metabolic panel
   • Serum ketones
   • Serum lactate
   • Serum osmolality (to calculate osmolal gap)
   • Urinalysis 2

2. Evaluate for Common Causes:

   • Check lactate levels for lactic acidosis
   • Test for ketones in blood and urine for ketoacidosis
   • Assess renal function for uremia
   • Calculate osmolal gap for toxic alcohol ingestion 6

3. Consider Less Common Causes:

   • 5-oxoprolinemia in patients with chronic acetaminophen use, especially with poor nutrition 3, 4
   • Inborn errors of metabolism in appropriate clinical context

Important Clinical Pearls

• An anion gap less than 20 mEq/L rarely has a defined etiology, but significant elevations almost always indicate an identifiable cause 1
• The presence of both an increased osmolal gap and metabolic acidosis strongly suggests toxic alcohol ingestion, but these findings can occur separately depending on the stage of metabolism 6
• Chronic acetaminophen use combined with poor nutrition can lead to glutathione depletion and subsequent 5-oxoproline accumulation, an often underrecognized cause of anion gap acidosis 3, 4
• Multiple causes can coexist, particularly in critically ill patients

Common Pitfalls to Avoid

• Relying solely on the "MUDPILES" mnemonic (Methanol, Uremia, Diabetic ketoacidosis, Paraldehyde, Isoniazid/Iron/Inborn errors, Lactic acidosis, Ethylene glycol, Salicylates) may lead to missing less common causes like 5-oxoprolinemia 4
• Failing to consider timing in toxic ingestions, as the anion gap may develop later as the parent compound is metabolized to organic acids
• Not calculating the osmolal gap when toxic alcohol ingestion is suspected
• Overlooking chronic medication use (like acetaminophen) as a potential cause of metabolic acidosis 3