What are the causes of elevated lactic acid levels?

Causes of Elevated Lactic Acid

Elevated lactic acid results primarily from tissue hypoperfusion and hypoxia causing anaerobic metabolism, but also occurs from impaired lactate clearance (liver/kidney disease), medication effects (especially metformin), and accelerated aerobic glycolysis from beta-adrenergic stimulation. 1

Primary Causes: Tissue Hypoperfusion and Hypoxia

The most common cause of elevated lactate is inadequate oxygen delivery to tissues, forcing cells into anaerobic metabolism. 1 This occurs in:

• Shock states (septic, cardiogenic, hypovolemic, distributive) where impaired tissue perfusion triggers lactate production 1, 2
• Sepsis and septic shock, where both tissue hypoperfusion and inflammatory mediators disrupt cellular metabolism 1
• Trauma with hemorrhagic shock, where lactate levels correlate directly with mortality risk 1
• Acute myocardial infarction, causing regional hypoperfusion and systemic inflammatory response 2
• Mesenteric ischemia (arterial embolism, thrombosis, venous thrombosis, or non-occlusive), where lactate >2 mmol/L with abdominal pain indicates a 4.1-fold increased risk of irreversible intestinal ischemia 1, 2

Medication-Induced Lactic Acidosis

Metformin is the most clinically significant medication cause of lactic acidosis, particularly dangerous in patients with impaired clearance. 3 The FDA specifies metformin causes lactic acidosis through:

• Impaired metformin clearance in renal impairment (eGFR <30 mL/min/1.73 m²) 4, 3
• Impaired lactate clearance in liver failure, as metformin decreases hepatic lactate uptake 3
• Conditions causing anaerobic metabolism including sepsis, hypoxia, acute heart failure, cardiovascular collapse, and shock 4, 3
• Higher risk in COVID-19 patients, with adjusted hazard ratio of 4.46 for lactic acidosis, especially with higher doses, worse kidney function, and severe disease 4

Epinephrine elevates lactate through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis independent of tissue perfusion. 1

High-dose vasopressors can cause non-occlusive mesenteric ischemia leading to lactic acidosis. 2

Impaired Lactate Clearance

• Liver disease impairs lactate clearance since the liver metabolizes up to 70% of lactate, causing accumulation even without increased production 2, 3
• Renal impairment reduces lactate clearance as kidneys contribute to lactate metabolism 3

Metabolic and Endocrine Causes

• Diabetic ketoacidosis (DKA) often presents with elevated lactate alongside ketoacidosis 2
• Thiamine deficiency impairs pyruvate metabolism, leading to lactate accumulation 2
• Glycogen storage disease type I causes persistently elevated lactate due to blocked gluconeogenesis; lactate rises rapidly when blood glucose drops 2, 5

Hypoxic States Without Shock

• Acute congestive heart failure with hypoperfusion and hypoxemia 3
• Respiratory failure causing tissue hypoxemia 1
• Carbon monoxide exposure impairing oxygen delivery 2
• Severe anemia reducing oxygen-carrying capacity 2

Other Important Causes

• Compartment syndrome restricting blood flow to tissues 2
• Seizures causing increased muscle lactate production 6
• Vigorous exercise when oxygen delivery cannot meet demand, occurring physiologically at 50-60% of predicted VO₂max 2
• Malignancy, particularly hematological malignancies 6, 7
• Toxins and drug overdose 6, 8

Critical Clinical Thresholds and Prognostic Significance

• Lactate >2 mmol/L indicates potential tissue hypoperfusion and warrants investigation 1
• Lactate >5 mmol/L is considered abnormal and requires urgent intervention 2, 3
• Lactate >10 mmol/L indicates serious, potentially life-threatening conditions 2
• Failure to normalize lactate within 24 hours drops survival to 77.8%, and to 13.6% if elevated beyond 48 hours 1

Critical Pitfalls to Avoid

Do not dismiss lactate 2-3 mmol/L with abdominal pain—this warrants immediate CT angiography for mesenteric ischemia even if the patient appears clinically stable. 1, 2 Delayed diagnosis is associated with irreversible intestinal ischemia and death.

Do not attribute all elevated lactate to sepsis—consider non-infectious causes including medications (especially metformin), liver disease, mesenteric ischemia, and beta-agonist effects. 2

Discontinue metformin immediately in patients with 4, 3:

• Acute kidney injury or eGFR <30 mL/min/1.73 m²
• Sepsis, hypoxia, or shock
• Acute heart failure
• Before iodinated contrast procedures (if eGFR 30-60 mL/min/1.73 m²)
• Hepatic impairment
• Excessive alcohol intake