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

Causes of Normal Anion Gap Metabolic Acidosis

Normal anion gap (NAG) metabolic acidosis results from either bicarbonate loss (gastrointestinal or renal) or impaired renal hydrogen ion excretion, with the reduction in bicarbonate balanced by a reciprocal increase in chloride concentration. 1

Primary Mechanisms

The pathophysiology involves loss of bicarbonate causing decreased extracellular volume, which triggers increased renal chloride reabsorption to maintain electroneutrality—this decreases the strong ion difference and lowers pH, creating the hyperchloremic pattern. 1

Major Causes

Gastrointestinal Bicarbonate Loss

• Diarrhea is the most common cause of NAG metabolic acidosis, resulting in direct bicarbonate loss through the GI tract. 2, 3
• Lower intestinal losses lead to bicarbonate depletion with compensatory chloride retention. 4, 3

Renal Tubular Acidosis (RTA)

• RTA Type 4 should be suspected in patients with significant hyperkalemia, especially diabetics with relatively preserved renal function. 2, 4
• RTA Type 1 and 2 result from intrinsic defects in the hydrogen ion pump or failure to generate favorable gradients for hydrogen ion secretion. 4
• A practical screening tool: consider RTA when the Cl⁻/Na⁺ ratio exceeds 0.79 in patients without diarrhea. 2

Drug-Induced Causes

• Carbonic anhydrase inhibitors (acetazolamide) directly impair bicarbonate reabsorption. 5
• Hydrochloride salts of amino acids provide an exogenous acid load. 5
• Spironolactone and NSAIDs can cause type 4 RTA through aldosterone antagonism or hyporeninemic hypoaldosteronism. 5, 4
• Amphotericin causes tubular dysfunction leading to RTA. 5
• Toluene exposure produces RTA. 5

Renal Causes

• Early renal failure before significant uremic acid accumulation presents with NAG acidosis. 3
• Hyporeninemic hypoaldosteronism (Type 4 RTA) is particularly common in diabetic patients and results in failure to augment hydrogen ion secretion due to reduced mineralocorticoids. 4

Recovery Phase of Diabetic Ketoacidosis

• DKA recovery produces transient NAG acidosis as chloride from IV fluids replaces ketoanions lost during osmotic diuresis—this is biochemically insignificant and requires no specific intervention unless acute renal failure or extreme oliguria develops. 1

Exogenous Acid Administration

• Administration of acidifying chloride salts or acids directly causes NAG acidosis. 6, 3

Diagnostic Approach

• Calculate the anion gap: [Na⁺] - ([Cl⁻] + [HCO₃⁻]), with normal being 8-12 mEq/L. 7
• Assess the Cl⁻/Na⁺ ratio—values >0.79 suggest RTA if diarrhea is absent. 2
• Evaluate for hyperkalemia to identify type 4 RTA, particularly in diabetic patients. 2, 4
• Obtain arterial blood gas to confirm metabolic acidosis (pH <7.35, bicarbonate <22 mmol/L). 8
• Review medication list for causative agents. 2, 5

Common Pitfalls

• Missing RTA diagnosis due to lack of familiarity—early identification remains challenging and treatment is often delayed. 2
• Overlooking medication-induced causes—a growing list of drugs can produce RTA. 2
• Misinterpreting DKA recovery phase—the transient NAG acidosis during recovery does not require bicarbonate therapy. 1
• Failing to check urinary chloride in metabolic alkalosis workup, which can help differentiate saline-responsive from saline-resistant causes when evaluating mixed disorders. 6