What are the causes of normal anion gap and anion gap metabolic acidosis?

Causes of Normal and Anion Gap Metabolic Acidosis

Metabolic acidosis can be categorized into normal anion gap (hyperchloremic) and high anion gap types, each with distinct etiologies that require different diagnostic and treatment approaches.

High Anion Gap Metabolic Acidosis

High anion gap metabolic acidosis occurs when there is accumulation of acids other than HCl, resulting in an anion gap typically >12 mEq/L. The classic mnemonic "MUDPILES" helps identify the causes:

Major Causes:

• Methanol: Ingestion leads to formation of formic acid 1
• Uremia: Accumulation of unmeasured anions in chronic kidney disease 2
• Diabetic ketoacidosis: Accumulation of ketoacids (β-hydroxybutyrate, acetoacetate) 1
• Propylene glycol/Paraldehyde: Toxic ingestions 1
• Isoniazid/Iron: Drug toxicities
• Lactic acidosis: From tissue hypoxia, sepsis, or metformin 1, 3
• Ethylene glycol: Ingestion leads to glycolate and oxalate formation 1
• Salicylates: Aspirin overdose 1

Additional Causes:

• Alcoholic ketoacidosis: Distinguished from DKA by lower glucose levels (rarely >250 mg/dL) 1
• Starvation ketosis: Usually with serum bicarbonate not lower than 18 mEq/L 1
• 5-Oxoproline accumulation: Associated with chronic acetaminophen use, especially in patients with risk factors like malnutrition, liver disease, or renal failure 4

Diagnostic Clues:

• Anion gap >12 mEq/L (calculated as Na⁺ - [Cl⁻ + HCO₃⁻])
• Severe cases may show anion gap >20-25 mEq/L 2
• Ethylene glycol and methanol poisoning often present with both elevated anion gap and osmolar gap 1, 5
• Metformin-associated lactic acidosis shows lactate levels >5 mmol/L and lactate:pyruvate ratio increase 3

Normal Anion Gap (Hyperchloremic) Metabolic Acidosis

Normal anion gap metabolic acidosis occurs when bicarbonate loss is accompanied by chloride retention, keeping the anion gap within normal range (8-12 mEq/L).

Major Causes:

1. Gastrointestinal bicarbonate loss:

   • Diarrhea (most common cause) 6
   • Small bowel or pancreatic drainage
   • Ureterosigmoidostomy, ileostomy 1

2. Renal Tubular Acidosis (RTA):

   • Type 1 (Distal) RTA: Defective H⁺ secretion in distal tubule
   • Type 2 (Proximal) RTA: Defective bicarbonate reabsorption
   • Type 4 RTA: Aldosterone deficiency or resistance, commonly seen in diabetic patients with hyperkalemia 7, 6

3. Medication-induced:

   • Carbonic anhydrase inhibitors (e.g., topiramate) 3
   • Various drugs causing RTA 6

4. Other causes:

   • Rapid IV saline administration (dilutional acidosis)
   • Recovery phase of diabetic ketoacidosis 1
   • Hyperalimentation
   • Ammonium chloride ingestion

Diagnostic Clues:

• Anion gap within normal range (8-12 mEq/L)
• Elevated chloride levels relative to sodium (Cl⁻/Na⁺ ratio >0.79 suggests RTA if diarrhea is absent) 6
• Hyperkalemia suggests Type 4 RTA, especially in diabetic patients 7

Clinical Approach to Differentiating Metabolic Acidosis

1. Calculate the anion gap: [Na⁺] - ([Cl⁻] + [HCO₃⁻])

   • Normal: 8-12 mEq/L
   • Elevated: >12 mEq/L

2. For high anion gap acidosis:

   • Calculate the Δ anion gap/ΔHCO₃⁻ ratio 5
   • Ratio = 1: Simple anion gap acidosis
   • Ratio < 1: Mixed anion gap and normal anion gap acidosis
   • Ratio > 1: Mixed anion gap acidosis and metabolic alkalosis

3. For normal anion gap acidosis:

   • Assess urinary anion gap to differentiate renal from extrarenal causes
   • Check urine pH (inappropriately alkaline urine in distal RTA)
   • Evaluate serum potassium (hyperkalemia suggests Type 4 RTA)

Pitfalls to Avoid

1. Overlooking mixed disorders: Multiple acid-base disturbances can coexist, especially in critically ill patients.

2. Failing to correct anion gap for hypoalbuminemia: Each 1 g/dL decrease in albumin decreases the anion gap by approximately 2.5 mEq/L.

3. Misinterpreting laboratory values: Some analyzers may falsely elevate lactate in ethylene glycol poisoning 1.

4. Delayed diagnosis of toxic ingestions: Prompt recognition of methanol or ethylene glycol poisoning is critical as hemodialysis may be life-saving 1.

5. Missing medication-related causes: Always review the patient's medication list for drugs that can cause or worsen metabolic acidosis 3, 6.