What are the causes of lactic acidosis?

Causes of Lactic Acidosis

Lactic acidosis is primarily caused by tissue hypoxia (Type A) or metabolic dysfunction (Type B), with circulatory disorders, severe infections, and medication toxicity being the most common etiologies. 1, 2

Classification of Causes

Type A Lactic Acidosis (Tissue Hypoxia)

• Circulatory disorders causing inadequate tissue perfusion:
  • Shock (cardiogenic, hypovolemic, septic) 1, 2, 3
  • Cardiac failure 2, 3
  • Severe hypotension 3
• Respiratory failure resulting in hypoxemia 3
• Severe anemia limiting oxygen-carrying capacity 3
• Acute mesenteric ischemia causing intestinal hypoperfusion 3
• Severe infections and sepsis causing tissue hypoperfusion and increased metabolic demands 2, 3
• Exercise beyond anaerobic threshold when oxygen delivery is insufficient to meet demand 3

Type B Lactic Acidosis (Metabolic Dysfunction)

• Medication-induced lactic acidosis:
  • Metformin, especially in patients with renal impairment (incidence 2-9/100,000 patients/year) 1, 2, 4
  • Nucleoside reverse transcriptase inhibitors (NRTIs) in HIV treatment, particularly stavudine and didanosine 1, 2
• Mitochondrial dysfunction:
  • NRTIs inhibiting DNA polymerase γ, responsible for mitochondrial DNA synthesis 1, 2, 3
  • Thiamine deficiency affecting pyruvate dehydrogenase function 3
• D-lactic acidosis in patients with short bowel syndrome and preserved colon 2, 3
• Liver disease impairing lactate clearance 5
• Excessive alcohol intake potentiating the effect of metformin on lactate metabolism 4

Pathophysiological Mechanisms

• Under normal conditions, lactate is produced during glycolysis and is metabolized by the liver 3
• In tissue hypoxia, anaerobic metabolism increases with conversion of pyruvate to lactate to regenerate NAD+ 3
• Metformin decreases liver uptake of lactate, increasing blood lactate levels 4
• Mitochondrial toxicity from medications like NRTIs inhibits DNA polymerase γ, leading to increased lactic acid production 1, 3

Clinical Presentation and Diagnosis

• Laboratory findings:
  • Arterial pH <7.3 (acidosis) 1, 3
  • Blood lactate levels >2 mmol/L (elevated), >5 mmol/L (abnormal), and >10 mmol/L (serious/life-threatening) 1, 2
  • Increased anion gap (Na - [Cl+CO2] >16) 1, 3
• Clinical symptoms:
  • Gastrointestinal: nausea, vomiting, abdominal pain 1, 3
  • Respiratory: tachypnea, dyspnea 1, 3
  • Neurological: weakness, confusion, altered mental status 3
  • General: myalgias, generalized weakness 1

Risk Factors for Specific Types of Lactic Acidosis

• Metformin-associated lactic acidosis:

  • Renal impairment (eGFR <45 mL/min/1.73 m²) 4
  • Age >65 years 1, 2
  • Congestive heart failure 1
  • Excessive alcohol intake 4
  • Radiologic studies with contrast agents 4
  • Hypoxic states (congestive heart failure, cardiovascular collapse, acute myocardial infarction, sepsis) 4
  • Surgery and procedures with restricted food and fluid intake 4

• Mesenteric ischemia-related lactic acidosis:

  • Atrial fibrillation 3
  • Recent myocardial infarction 3
  • Cardiac failure 3
  • Diffuse atherosclerotic disease 3
  • Elevated D-dimer (>0.9 mg/L) 3

• D-lactic acidosis:

  • Short bowel syndrome with preserved colon 2, 3

Diagnostic Considerations

• Proper lactate measurement requires:

  • Prechilled fluoride-oxalate tubes 1, 2
  • Transport on ice to laboratory 1, 2
  • Processing within 4 hours of collection 1, 2
  • Collection without tourniquet or fist-clenching 1, 2

• Evaluating for underlying causes includes:

  • Assessing hemodynamic status and tissue perfusion 2
  • Reviewing medication history 2
  • Evaluating liver and kidney function 2