What are the causes of Non-Anion Gap Metabolic Acidosis (NAGMA)?

Causes of Non-Anion Gap Metabolic Acidosis (NAGMA)

Non-Anion Gap Metabolic Acidosis (NAGMA) is primarily caused by bicarbonate loss from the gastrointestinal tract, renal tubular acidosis, and certain medications or toxins that disrupt acid-base balance. 1

Classification of NAGMA Causes

1. Gastrointestinal Bicarbonate Loss

• Diarrhea - most common cause of NAGMA in clinical practice 2
• High-volume ileostomy output - causing large bicarbonate losses 3
• Ileal neobladder/urinary diversion - surgical consequence that predisposes to chronic acid load and bicarbonate deficit 4
• Pancreatic or biliary fistulas - leading to bicarbonate-rich secretion loss
• Ureterosigmoidostomy - causing chloride absorption and bicarbonate secretion

2. Renal Causes

• Renal Tubular Acidosis (RTA):
  • Type 1 (Distal) RTA - impaired H+ secretion in distal tubule
  • Type 2 (Proximal) RTA - decreased bicarbonate reabsorption in proximal tubule
  • Type 4 RTA - hypoaldosteronism leading to impaired NH4+ excretion and hyperkalemia
• Early renal failure - before significant anion retention occurs 2
• Carbonic anhydrase inhibitors (e.g., acetazolamide) - causing renal loss of HCO3- ion, which carries out sodium, water, and potassium 5

3. Medication and Toxin-Induced

• Carbonic anhydrase inhibitors (acetazolamide) - inhibit the enzyme that catalyzes CO2 hydration and carbonic acid dehydration 5
• Hyperalimentation solutions - containing cationic amino acids (lysine, arginine)
• Acid administration - ammonium chloride, hydrochloric acid
• Cholestyramine - bile acid sequestrant that can cause metabolic acidosis 6

4. Other Causes

• D-lactic acidosis - occurs in patients with short bowel and preserved colon; colonic bacteria degrade fermentable carbohydrates to form D-lactate 6
• Hyperammonemia - in short bowel syndrome when ammonia cannot be detoxified due to insufficient citrulline production 6
• Dilutional acidosis - rapid expansion of extracellular fluid with non-bicarbonate containing solutions
• Recovery phase of diabetic ketoacidosis - as ketoacids are metabolized to bicarbonate

Diagnostic Approach

1. Confirm NAGMA: Metabolic acidosis with normal anion gap (8-12 mEq/L) 1
2. Assess serum potassium:
   • Hyperkalemic NAGMA suggests Type 4 RTA or early renal failure
   • Hypokalemic NAGMA suggests GI losses, Type 1 or 2 RTA 7
3. Measure urine pH:
   • Urine pH <5.5 with acidemia suggests normal renal acidification (pointing to GI losses)
   • Urine pH >5.5 with acidemia suggests defective renal acidification (RTA) 7
4. Evaluate urine ammonium excretion - directly or indirectly to differentiate between renal and non-renal causes 7

Clinical Pearls

• NAGMA often coexists with high anion gap metabolic acidosis in mixed disorders 7
• Severe diarrhea can cause both NAGMA and acute kidney injury, complicating the clinical picture 8
• Choice of resuscitation fluid matters - normal saline can worsen hyperchloremic acidosis compared to balanced crystalloids like Ringer's lactate 8
• Patients with ileal neobladder are particularly susceptible to severe NAGMA during urinary tract infections 4
• Treatment should address the underlying cause rather than just correcting the acidosis with bicarbonate therapy 2

Remember that a systematic approach to differential diagnosis of NAGMA, including thorough history, physical examination, and targeted laboratory testing, is essential for accurate diagnosis and appropriate management.