What are the causes of metabolic acidosis, including high‑anion‑gap and normal‑anion‑gap etiologies?

Metabolic Acidosis: Causes and Classification

Primary Classification by Anion Gap

Metabolic acidosis is classified into high anion-gap and normal anion-gap (hyperchloremic) etiologies based on the anion gap calculation: [Na⁺] − ([HCO₃⁻] + [Cl⁻]), with normal values of 10–12 mEq/L. 1

High Anion-Gap Metabolic Acidosis (Anion Gap >12 mEq/L)

An elevated anion gap signifies accumulation of unmeasured anions such as lactate, ketoacids, uremic toxins, or ingested toxins. 1 The primary causes include:

Lactic Acidosis:

• Results from inadequate oxygen delivery to tissues and tissue hypoperfusion in shock states 2
• Lactate levels >2 mmol/L indicate tissue hypoxia and correlate with mortality 3
• Most common cause in critically ill patients with septic shock, cardiogenic shock, or hemorrhagic shock 3

Ketoacidosis:

• Diabetic ketoacidosis (DKA): Characterized by plasma glucose >250 mg/dL, arterial pH <7.3, bicarbonate <15 mEq/L, and positive serum/urine ketones 4, 2
• Alcoholic ketoacidosis (AKA): Distinguished by plasma glucose rarely >250 mg/dL (often hypoglycemic) and clinical history of alcohol use 4, 2
• Starvation ketosis: Serum bicarbonate usually not lower than 18 mEq/L with mildly elevated glucose 4, 2

Chronic Kidney Disease:

• Develops when GFR decreases to <20–25% of normal 5
• Plasma bicarbonate typically ranges from 12–22 mEq/L 5
• Can present as high anion-gap acidosis due to impaired renal acid excretion, though anion gap may be normal or only moderately increased even with stage 4–5 CKD 2, 5

Toxic Ingestions:

• Salicylate, methanol, ethylene glycol, and paraldehyde ingestion 4
• Osmolal gap is elevated in methanol, ethylene glycol, and propylene glycol ingestions 2

Normal Anion-Gap (Hyperchloremic) Metabolic Acidosis

Normal anion-gap acidosis occurs when bicarbonate is lost or replaced by chloride, maintaining electroneutrality. 6 The key causes include:

Gastrointestinal Bicarbonate Loss:

• Diarrhea: Acute watery diarrhea from infectious gastroenteritis (viral, bacterial, parasitic), inflammatory bowel disease (ulcerative colitis, Crohn's disease), celiac disease with malabsorption, or medication-induced diarrhea (magnesium-containing products, metformin, NSAIDs) 1
• Bicarbonate is lost directly through stool 1

Renal Tubular Acidosis (RTA):

• Proximal RTA (Type 2): Filtered bicarbonate is lost by kidney wasting due to impaired proximal tubular bicarbonate reabsorption 6
• Distal RTA (Type 1): Renal input of new bicarbonate is insufficient to regenerate bicarbonate lost in buffering endogenous acid due to impaired distal hydrogen ion secretion 6
• RTA of renal insufficiency (Type 4): Characterized by hyperkalemia and impaired ammonium excretion 6
• Assessment of urinary ammonium excretion by calculating the urine anion gap or osmolal gap distinguishes renal from extrarenal causes 6

Iatrogenic Causes:

• Large-volume 0.9% saline administration: Produces dilutional hyperchloremic acidosis by increasing serum chloride and decreasing the strong ion difference, impairing renal blood flow and promoting sodium retention 1
• Unbalanced colloid solutions during cardiopulmonary bypass 1

Recovery Phase of DKA:

• As ketoacids are metabolized and excreted, chloride is retained to maintain electroneutrality, resulting in a transient normal anion-gap acidosis 1

Diagnostic Approach Algorithm

1. Confirm metabolic acidosis: pH <7.35, bicarbonate <22 mmol/L 1, 7

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

3. If anion gap >12 mEq/L (high anion-gap acidosis):

   • Measure blood lactate to assess for lactic acidosis 2
   • Check serum/urine ketones to distinguish ketoacidosis 4, 2
   • Obtain plasma glucose: >250 mg/dL suggests DKA; mildly elevated or low suggests AKA or starvation 4, 2
   • Calculate osmolal gap if toxic ingestion suspected 2
   • Assess renal function (BUN/creatinine) for uremic acidosis 4

4. If anion gap ≤12 mEq/L (normal anion-gap acidosis):

   • Assess clinical history for diarrhea or recent large-volume saline administration 1, 6
   • Calculate urine anion gap or osmolal gap to distinguish renal from extrarenal causes 6
   • Check serum potassium: hyperkalemia suggests Type 4 RTA; hypokalemia suggests Type 1 or 2 RTA 6
   • Measure urine pH: >5.5 in acidosis suggests proximal RTA or diarrhea; inability to acidify urine (<5.5) suggests distal RTA 6

Special Clinical Contexts

Septic Shock:

• Exhibits complex metabolic acidosis with multiple contributors including lactic acidosis, hyperchloremic acidosis from resuscitation fluids, and increased strong ion gap 2

Chronic Dietary-Induced Acidosis:

• Western diet high in animal protein (containing sulfur-containing amino acids that produce nonvolatile acids) and low in fruits/vegetables (which provide potassium citrate salts generating alkali) leads to chronic low-grade metabolic acidosis 1, 2

Critical Pitfalls to Avoid

• Do not assume a single cause: Mixed acid-base disorders are common, particularly in critically ill patients where high anion-gap and normal anion-gap acidosis can coexist 4
• Do not overlook iatrogenic hyperchloremic acidosis: Large-volume normal saline resuscitation is a frequent and preventable cause; switch to balanced crystalloids (Lactated Ringer's or Plasma-Lyte) to avoid additional chloride loading 1
• Do not delay evaluation of life-threatening causes: Septic shock, mesenteric ischemia, toxic ingestions, and DKA require immediate specific interventions 3
• Do not confuse serum CO₂ on basic metabolic panel with arterial PCO₂: The CO₂ measurement reflects total carbon dioxide content (predominantly bicarbonate), not respiratory status 1