What are the causes of normal anion gap metabolic acidosis (NAGMA)?

Causes of Normal Anion Gap Metabolic Acidosis (NAGMA)

Normal anion gap metabolic acidosis results from either gastrointestinal bicarbonate loss, renal bicarbonate wasting, impaired renal acid excretion, or exogenous acid administration—with the reduction in bicarbonate balanced by a reciprocal increase in chloride concentration. 1, 2

Primary Mechanisms of NAGMA

NAGMA occurs when bicarbonate is effectively replaced by chloride, maintaining electroneutrality while producing acidosis. 2, 3 The three fundamental pathways are:

• Loss of bicarbonate-rich fluids from the gastrointestinal tract or kidneys 4
• Impaired renal hydrogen ion excretion despite intact bicarbonate reabsorption 1
• Exogenous chloride loading that dilutes bicarbonate stores 5

Gastrointestinal Causes

Diarrhea is the most common cause of NAGMA in clinical practice. 1 Specific etiologies include:

• Acute watery diarrhea from infectious gastroenteritis (viral, bacterial, or parasitic) causes direct bicarbonate loss in stool 1
• Inflammatory bowel diseases (ulcerative colitis, Crohn's disease) produce sufficient bicarbonate loss to generate hyperchloremic acidosis 1
• Celiac disease with malabsorption can precipitate NAGMA via diarrheal bicarbonate loss 1
• Medication-induced diarrhea from magnesium-containing products, metformin, or NSAIDs 1

Renal Tubular Acidosis (RTA)

The kidneys can fail to excrete acid or waste bicarbonate, producing NAGMA:

• Proximal (Type 2) RTA is characterized by impaired proximal tubular bicarbonate reabsorption and is commonly linked to Fanconi syndrome with concurrent urinary losses of phosphate, uric acid, glucose, and amino acids 6
• Distal (Type 1) RTA results from impaired distal tubular hydrogen ion secretion 1
• Type 4 RTA occurs with aldosterone deficiency or resistance, typically presenting with hyperkalemia 1

Chronic Kidney Disease

CKD impairs the kidney's ability to excrete hydrogen ions and synthesize ammonia, leading to acid accumulation. 1 Key features include:

• Early-to-moderate CKD (stages 3-4) typically presents with NAGMA before progressing to high anion gap acidosis in stage 5 1
• Dietary factors contribute: Western diets high in animal protein and low in fruits/vegetables create an imbalance between nonvolatile acids and available alkali 1, 6
• A markedly low BUN-to-creatinine ratio (≈0.8) effectively rules out stage V CKD, which characteristically shows a ratio >20:1 6

Iatrogenic Causes

Large-volume 0.9% saline infusion produces dilutional hyperchloremic metabolic acidosis by increasing serum chloride and decreasing the strong ion difference. 1 This mechanism:

• Impairs renal blood flow and promotes sodium retention 1
• Creates a self-reinforcing cycle where excess chloride replaces lost bicarbonate 1
• Is particularly common during cardiopulmonary bypass or aggressive resuscitation 1

Medications and Toxins

Several pharmacologic agents cause NAGMA:

• Carbonic anhydrase inhibitors (acetazolamide, topiramate) block proximal tubular bicarbonate reabsorption 2
• Hydrochloride salts of amino acids (arginine HCl, lysine HCl) provide exogenous acid load 2
• Toluene inhalation initially causes high anion gap acidosis that converts to NAGMA as hippurate is excreted 2
• Amphotericin B causes distal RTA through tubular toxicity 2
• Spironolactone can produce Type 4 RTA 2
• Non-steroidal anti-inflammatory drugs may cause Type 4 RTA 2

Diagnostic Algorithm

To identify the cause of NAGMA:

1. Calculate the anion gap: Na⁺ − (HCO₃⁻ + Cl⁻); normal is 10-12 mEq/L 1, 7
2. Assess for gastrointestinal losses: History of diarrhea, ileostomy, or ureterosigmoidostomy 1
3. Evaluate renal function: BUN, creatinine, and BUN/creatinine ratio to assess CKD stage 6
4. Check urine pH and electrolytes: Urine pH >5.5 in acidosis suggests distal RTA; urine anion gap helps differentiate renal from GI losses 1
5. Review medication list: Identify potential causative agents 2
6. Assess for Fanconi syndrome markers: Hypophosphatemia, hypouricemia, glycosuria, and aminoaciduria suggest proximal RTA 6

Common Clinical Pitfalls

• Overlooking iatrogenic saline-induced acidosis during aggressive resuscitation—switch to balanced crystalloids (Lactated Ringer's or Plasma-Lyte) to prevent additional chloride loading 1
• Failing to recognize mixed disorders: Critically ill patients commonly have concurrent high-anion-gap and normal-anion-gap acidosis 6
• Misinterpreting compensated respiratory acidosis as primary metabolic alkalosis—obtain arterial blood gas to measure pH and PaCO₂ for definitive differentiation 1