What are the causes of metabolic acidosis?

Causes of Metabolic Acidosis

Metabolic acidosis can be caused by failure to excrete acids produced by normal metabolic processes (e.g., renal failure), increased production of acids from abnormal metabolic conditions (e.g., diabetic ketoacidosis), or direct loss of bicarbonate from the kidney or gut (e.g., chronic diarrhea). 1

Classification by Anion Gap

High Anion Gap Metabolic Acidosis

• Diabetic ketoacidosis (DKA): Results from insulin deficiency with elevated counterregulatory hormones, leading to increased production of ketone bodies (β-hydroxybutyrate and acetoacetate) 1, 2
• Lactic acidosis: Caused by tissue hypoxia due to decreased oxygen delivery or impaired oxygen utilization, commonly seen in shock states, severe hypoxemia, or during peak exercise 1, 2
• Renal failure: Leads to accumulation of organic acids and impaired acid excretion, typically presenting with elevated BUN, creatinine, and hyperkalemia 2, 3
• Toxin ingestion:
  • Methanol: Produces both anion gap and osmolar gap due to being a low-molecular weight organic compound 2
  • Ethylene glycol: Metabolized to glycolic and oxalic acids 4
  • Salicylate poisoning: Causes uncoupling of oxidative phosphorylation 2, 4
• Pyroglutamic acidosis (5-oxoproline): Less common cause, can be associated with certain medications 3
• Propylene glycol toxicity: Found in some intravenous medications 3

Normal Anion Gap (Hyperchloremic) Metabolic Acidosis

• Gastrointestinal bicarbonate loss: Diarrhea, pancreatic or biliary fistulas, ureterosigmoidostomy 3, 5
• Renal tubular acidosis (RTA):
  • Type I (distal) RTA: Impaired H+ secretion in distal tubule 4, 5
  • Type II (proximal) RTA: Decreased bicarbonate reabsorption 4
  • Type IV RTA: Hypoaldosteronism leading to impaired acid excretion, often seen in diabetic patients 6, 4
• Drug-induced hyperkalemia: Can lead to hyperchloremic acidosis 2, 4
• Early renal failure: Before significant accumulation of organic acids 3
• Administration of acids or acid precursors: Ammonium chloride, arginine hydrochloride 4, 3

Diagnostic Approach

• Calculate anion gap: [Na+] - ([Cl-] + [HCO3-]), with normal being 8-12 mEq/L; high anion gap is >12 mEq/L 2
• Assess osmolal gap to detect presence of low molecular weight toxins like methanol and ethylene glycol 2
• Evaluate urine pH and serum potassium levels to help differentiate causes 7
• Measure blood lactate when lactic acidosis is suspected 2
• Laboratory analysis of organic acids can help identify specific causes, particularly in cases of inborn errors of metabolism 2

Common Clinical Scenarios

• In diabetic patients, metabolic acidosis may present as:

  • Ketoacidosis: Due to insulin deficiency and increased counterregulatory hormones 1, 6
  • Lactic acidosis: Particularly in patients on metformin or with tissue hypoperfusion 6, 4
  • Hyperchloremic acidosis: From renal tubular dysfunction 6
  • Type IV renal tubular acidosis: Due to hypoaldosteronism 6

• Drug-induced metabolic acidosis:

  • Biguanides (metformin): Can cause lactic acidosis, especially with renal impairment 4
  • Antiretrovirals: Associated with lactic acidosis 4
  • Salicylates: Cause mixed respiratory alkalosis and metabolic acidosis 4, 3
  • Acetazolamide and topiramate: Can induce proximal RTA 4

• Chemical exposure:

  • Ethylene glycol and methanol: Produce toxic metabolites causing severe anion gap acidosis 2, 3
  • Toluene: Can cause distal RTA 3

Clinical Pearls

• The presence of an increased anion gap is a crucial first step in determining the etiology of metabolic acidosis 5
• In high anion gap metabolic acidosis, the rise in anion gap usually equals the fall in plasma bicarbonate 6
• Mixed acid-base disorders are common, particularly in critically ill patients 3
• Progressive decline in the anion gap is one of the best indicators of successful treatment in high anion gap metabolic acidosis 6