What are the causes of lactic acidosis?

Causes of Lactic Acidosis

Lactic acidosis is primarily caused by tissue hypoxia resulting from decreased oxygen delivery or impaired cellular oxygen utilization, with additional causes including medication effects, metabolic disorders, and specific disease states.

Classification of Lactic Acidosis

Type A (Hypoxic) Lactic Acidosis

• Circulatory disorders including shock, cardiac failure, and severe hypotension lead to inadequate tissue perfusion and oxygen delivery 1, 2
• Severe infections and sepsis cause tissue hypoperfusion and increased metabolic demands 2, 3
• Acute mesenteric ischemia can cause lactic acidosis due to intestinal hypoperfusion 1
• Respiratory failure resulting in hypoxemia 1
• Severe anemia limiting oxygen-carrying capacity 2
• Exercise beyond anaerobic threshold when oxygen delivery is insufficient to meet demand 1

Type B (Non-Hypoxic) Lactic Acidosis

• Medication-induced:
  • Metformin, especially in patients with renal impairment, with an incidence of 2-9/100,000 patients/year 2, 4
  • Nucleoside reverse transcriptase inhibitors (NRTIs) in HIV treatment, particularly stavudine and didanosine 2, 3
• Metabolic disorders:
  • Thiamine deficiency affecting pyruvate dehydrogenase function 2, 5
  • D-lactic acidosis in patients with short bowel syndrome and preserved colon 2
• Liver disease impairing lactate clearance 4
• Malignancies causing increased glycolysis 2, 5
• Inherited enzymatic defects affecting lactate metabolism 3

Pathophysiological Mechanisms

• Under normal conditions, lactate is produced during glycolysis and is metabolized by the liver 1, 2
• In tissue hypoxia, anaerobic metabolism increases with conversion of pyruvate to lactate to regenerate NAD+ 1
• Mitochondrial dysfunction can occur due to:
  • NRTIs inhibiting DNA polymerase γ, responsible for mitochondrial DNA synthesis 2
  • Thiamine deficiency affecting pyruvate dehydrogenase function 2
• Metformin decreases liver uptake of lactate, increasing blood lactate levels 4
• The liver is the primary site for lactate clearance, with kidneys contributing to a lesser extent 6

Clinical Presentation and Diagnosis

Laboratory Findings

• Arterial pH <7.35 (acidosis) 1, 2
• Blood lactate levels >2 mmol/L (elevated), >5 mmol/L (abnormal), and >10 mmol/L (serious/life-threatening) 2, 3
• Increased anion gap (Na - [Cl+HCO3-] >16) 2
• Elevated serum lactate with normal pyruvate levels results in increased lactate:pyruvate ratio 4

Clinical Symptoms

• Gastrointestinal symptoms: nausea, vomiting, abdominal pain 3
• Respiratory symptoms: tachypnea, dyspnea (compensatory respiratory alkalosis) 2, 3
• Neurological symptoms: weakness, confusion, altered mental status 2
• In severe cases: hypotension and resistant bradyarrhythmias 4

Risk Factors for Specific Types of Lactic Acidosis

Metformin-Associated Lactic Acidosis

• Renal impairment (eGFR <45 mL/min/1.73m²) 4
• Age >65 years 3, 4
• Hepatic impairment 4
• Congestive heart failure 4
• Excessive alcohol intake 4
• Radiologic studies with iodinated contrast agents 4
• Surgery and procedures with restricted food and fluid intake 4
• Hypoxic states (acute heart failure, myocardial infarction, sepsis) 4

Mesenteric Ischemia-Related Lactic Acidosis

• Atrial fibrillation 1
• Recent myocardial infarction 1
• Cardiac failure 1
• Diffuse atherosclerotic disease 1

Diagnostic Considerations

• Proper lactate measurement requires:
  • Prechilled fluoride-oxalate tubes
  • Transport on ice to laboratory
  • Processing within 4 hours of collection
  • Collection without tourniquet or fist-clenching 2, 3
• Elevated D-dimer (>0.9 mg/L) may be an independent risk factor for intestinal ischemia causing lactic acidosis 1
• Evaluate for underlying causes by assessing:
  • Hemodynamic status and tissue perfusion
  • Medication history
  • Liver and kidney function 2

Special Populations at Risk

• Elderly patients (>65 years) have higher risk for metformin-associated lactic acidosis 3
• Patients with short bowel syndrome and preserved colon are at risk for D-lactic acidosis 2
• Patients with underlying renal or hepatic dysfunction 4
• Critically ill patients with multi-organ failure 7

Common Pitfalls in Diagnosis

• Failing to recognize non-hypoxic (Type B) causes when hypoxic (Type A) causes seem more apparent 5
• Overlooking medication-induced lactic acidosis, especially in patients on metformin with declining renal function 4
• Not considering thiamine deficiency in patients with malignancy 5
• Misinterpreting normal lactate levels in the presence of severe acidosis due to delayed processing of samples 2, 3