What are the causes of lactic acidosis?

Causes of Lactic Acidosis

Lactic acidosis is primarily caused by either increased production or decreased clearance of lactic acid, with the most common clinical presentation being a broad-anion gap metabolic acidosis. 1

Classification of Lactic Acidosis

Type A Lactic Acidosis (Tissue Hypoxia)

• Occurs when the body must regenerate ATP without oxygen due to tissue hypoxia 1
• Common causes include:
  • Circulatory disorders (shock, cardiac failure) 2, 1
  • Pulmonary disorders (respiratory failure, severe hypoxemia) 2, 3
  • Hemoglobin transfer disorders 1
  • Sepsis 3
  • Cardiovascular collapse 3
  • Acute myocardial infarction 3

Type B Lactic Acidosis (Without Tissue Hypoxia)

• Occurs without evidence of tissue hypoxemia 4
• Common causes include:

B1: Underlying Diseases

• Diabetes mellitus 2
• Liver disease/failure (impaired lactate clearance) 3, 1
• Renal failure 3
• Malignancies 1, 4
• Severe infections 2
• Hereditary enzymatic defects 4
• Hematological malignancies 4

B2: Medication/Toxin-Induced

• Metformin (especially with renal impairment) 2, 3
• Nucleoside reverse transcriptase inhibitors (NRTIs) in HIV treatment 2
  • Particularly stavudine and didanosine 2
• Cyanide poisoning 1
• Alcohol (excessive intake) 3
• Historical: Phenformin (biguanide withdrawn from market) 4

B3: Inborn Errors of Metabolism

• Pyruvate dehydrogenase deficiency 1
• Thiamine deficiency 1
• Mitochondrial disorders 2

Pathophysiological Mechanisms

Increased Production

• Anaerobic glycolysis during tissue hypoxia 1
• Accelerated aerobic glycolysis (e.g., in sepsis, malignancies) 1, 4
• Inhibition of pyruvate dehydrogenase 1
• Mitochondrial toxicity (e.g., from NRTIs) 2
  • NRTIs inhibit DNA polymerase γ, responsible for mitochondrial DNA synthesis 2

Decreased Clearance

• Liver dysfunction (primary site of lactate clearance) 1
• Renal impairment (kidneys contribute to lactate removal) 3, 1
• Medications that impair lactate metabolism 3

Special Clinical Scenarios

Metformin-Associated Lactic Acidosis

• Rare but serious side effect (incidence: 2-9/100,000 patients/year) 1
• Risk factors include:
  • Renal impairment (eGFR <30 mL/min/1.73m²) 3
  • Advanced age (>65 years) 2, 3
  • Hepatic impairment 3
  • Congestive heart failure 2, 3
  • Excessive alcohol intake 3
  • Iodinated contrast procedures 3
  • Hypoxic states 3
  • Surgery or procedures with restricted food/fluid intake 3

HIV Treatment-Associated Lactic Acidosis

• Associated with nucleoside analog drugs, especially stavudine and didanosine 2
• Risk factors include:
  • Female gender 2
  • Obesity 2
  • Prolonged NRTI use 2
  • Pregnancy (particularly third trimester) 2

Euglycemic Diabetic Ketoacidosis with Lactic Acidosis

• Rare complication that can occur with metformin overdose 5
• Contributing factors include:
  • Diabetes mellitus 5
  • Starvation 5
  • Infection 5
  • Stressful physical conditions 5

Clinical Presentation and Diagnosis

• Laboratory findings:
  • Arterial pH <7.3 4
  • Blood lactate >2 mEq/L (or >2 mmol/L) 4
  • Increased anion gap (Na - [Cl+CO2] >16) 2
  • Often elevated aminotransferases, creatine phosphokinase, lactic dehydrogenase 2
• Clinical symptoms (often nonspecific):
  • Nausea, vomiting, abdominal pain 2, 3
  • Dyspnea, tachypnea 2
  • Generalized weakness 2, 3
  • Altered mental status, somnolence 3
  • Myalgias, paresthesias 2
  • In severe cases: hypotension, bradyarrhythmias 3

Monitoring Considerations

• Proper lactate measurement requires:
  • Prechilled fluoride-oxalate tubes 2
  • Transport on ice to laboratory 2
  • Processing within 4 hours of collection 2
  • Collection without tourniquet or fist-clenching 2
• Interpretation of serum lactate:
  • 2-5 mmol/L: elevated (correlate with symptoms) 2

  • 5 mmol/L: abnormal 2

  • 10 mmol/L: serious/life-threatening 2

Management Principles

• Treat underlying cause 1, 4
• Discontinue offending medications 2, 3
• Supportive care including:
  • Bicarbonate infusions for severe acidosis 2
  • Hemodialysis (especially for metformin-associated lactic acidosis) 2, 3
  • Mechanical ventilation if respiratory failure develops 2
• Consider thiamine and riboflavin supplementation in specific cases 2