What are the causes of metabolic acidosis?

Causes of Metabolic Acidosis

Metabolic acidosis arises from three fundamental mechanisms: excessive acid production, impaired renal acid excretion, or bicarbonate loss—and the first diagnostic step is determining whether an anion gap is present. 1

Classification by Anion Gap

The anion gap distinguishes between two major categories of metabolic acidosis and guides your differential diagnosis:

High Anion Gap Metabolic Acidosis (Unmeasured Organic Anions Present)

Lactic acidosis is the most common cause in critically ill patients, resulting from tissue hypoperfusion and inadequate oxygen delivery in shock states. 1, 2 Serial lactate measurements provide critical information about shock severity and treatment response. 1

Ketoacidosis presents in three distinct forms that require differentiation by plasma glucose and clinical history: 1

• Diabetic ketoacidosis (DKA): Plasma glucose typically >250 mg/dL, arterial pH <7.3, serum bicarbonate <15 mEq/L, and positive serum/urine ketones 1
• Alcoholic ketoacidosis (AKA): Plasma glucose low or normal (rarely >250 mg/dL) with recent heavy alcohol use 1
• Starvation ketosis: Serum bicarbonate ≥18 mEq/L with only mildly elevated glucose 1

Chronic kidney disease causes high anion gap acidosis when impaired renal acid excretion allows accumulation of unmeasured anions. 1 As glomerular filtration rate declines severely, the anion gap widens. 3

Toxic ingestions including salicylates, methanol, ethylene glycol, and paraldehyde produce high anion gap acidosis. 1 Calculate the osmolal gap when these ingestions are suspected—it will be elevated in methanol, ethylene glycol, and propylene glycol poisoning. 1

Rare organic acidemias such as methylmalonic acidemia, propionic acidemia, and isovaleric acidemia present with high anion gap acidosis, typically manifesting as toxic encephalopathy with vomiting and neurologic symptoms in children. 1, 4

Normal Anion Gap (Hyperchloremic) Metabolic Acidosis

Gastrointestinal bicarbonate loss from diarrhea, ileostomy, or ureterosigmoidostomy causes hyperchloremic acidosis because chloride is retained to maintain electroneutrality as bicarbonate is lost. 3

Renal tubular acidosis (RTA) results from primary defects in renal acidification: 3

• Proximal RTA (Type 2): Impaired proximal tubule bicarbonate reabsorption, commonly associated with Fanconi syndrome (concurrent urinary losses of phosphate, uric acid, glucose, and amino acids) 1
• Distal RTA (Type 1): Impaired distal tubule hydrogen ion secretion; a blood urea nitrogen-to-creatinine ratio ≈0.8 effectively excludes advanced chronic kidney disease as the cause 1
• RTA of renal insufficiency: Insufficient new bicarbonate generation to buffer endogenous acid production 3

Rapid saline administration can induce hyperchloremic acidosis by diluting bicarbonate and increasing chloride concentration. 2

Drug-induced acidosis occurs through various mechanisms depending on the specific agent. 5

Special Clinical Contexts

Septic shock exhibits complex metabolic acidosis with multiple simultaneous contributors: lactic acidosis from tissue hypoperfusion, hyperchloremic acidosis from resuscitation fluids, and increased strong ion gap. 1, 2

Dietary-induced chronic low-grade acidosis develops with high animal protein intake and low fruit/vegetable consumption, creating an imbalance between nonvolatile acid production and available alkali. 1

Diagnostic Algorithm

When metabolic acidosis is identified (pH <7.35, serum bicarbonate <22 mmol/L), proceed systematically: 6, 7

1. Calculate the anion gap to categorize the acidosis 7

2. For high anion gap acidosis, measure: 1

   • Blood lactate (essential in shock states)
   • Serum or urine ketones (to identify ketoacidosis)
   • Plasma glucose (to distinguish DKA from AKA/starvation)
   • Renal function (BUN/creatinine for uremic acidosis)
   • Osmolal gap (if toxic ingestion suspected)

3. For normal anion gap acidosis, assess: 3

   • Urine anion gap or osmolal gap (to distinguish renal from extrarenal causes)
   • Urine pH (low in extrarenal causes, inappropriately high in distal RTA)
   • Serum potassium (helps differentiate RTA types)
   • Clinical history for gastrointestinal losses or drug exposures

4. Search actively for mixed acid-base disorders in critically ill patients, as concurrent high anion gap and normal anion gap acidosis are common rather than assuming a single etiology. 1

Critical Pitfalls to Avoid

Do not assume a single cause in complex patients—septic shock, for example, frequently combines lactic acidosis with hyperchloremic acidosis from resuscitation. 2

Do not overlook life-threatening etiologies such as mesenteric ischemia, toxic ingestions, or septic shock that require immediate specific interventions beyond supportive care. 2

Monitor serial measurements of lactate, pH, and base deficit every 1-2 hours initially to assess treatment response and shock severity. 2

Recognize that chronic kidney disease initially presents with normal anion gap acidosis, but severe reductions in glomerular filtration rate eventually produce anion gap acidosis. 3