What are the common causes of elevated lactic acid (lactic acidosis)?

Elevated Lactic Acid: Common Causes

Elevated lactic acid results most commonly from tissue hypoperfusion and hypoxia (Type A lactic acidosis), but can also occur from metabolic disturbances, medications, and organ dysfunction without hypoxia (Type B lactic acidosis). 1, 2

Type A Lactic Acidosis: Tissue Hypoperfusion and Hypoxia

Type A lactic acidosis occurs when tissues cannot receive adequate oxygen, forcing cells into anaerobic metabolism. 1, 2

Circulatory Causes

• Sepsis and septic shock are major causes, producing lactic acidosis through both tissue hypoperfusion and inflammatory mediators affecting cellular metabolism. 1, 2 Sepsis-induced tissue hypoperfusion is defined as hypotension persisting after initial fluid challenge OR blood lactate ≥4 mmol/L. 2
• All shock states lead to impaired tissue perfusion, including hypovolemic shock (hemorrhage, dehydration), cardiogenic shock (myocardial infarction, heart failure), and distributive shock. 1, 2, 3
• Trauma with hemorrhagic shock produces lactate elevation that correlates directly with mortality. 2 More than 88% of patients with acute mesenteric ischemia present with metabolic acidosis and elevated lactate. 1, 2

Respiratory and Hematologic Causes

• Severe hypoxemia and respiratory failure reduce oxygen delivery to tissues. 3
• Severe anemia impairs oxygen-carrying capacity. 4

Type B Lactic Acidosis: Metabolic and Non-Hypoxic Causes

Type B lactic acidosis occurs without tissue hypoxia, resulting from metabolic disturbances, drug toxicity, or organ dysfunction. 1, 3

Medication-Induced Causes

• Metformin is the most clinically significant drug cause, with an incidence of 2-9 per 100,000 patients/year. 1 Risk dramatically increases with renal impairment (eGFR <30 mL/min/1.73 m²), sepsis, hypoxia, or liver failure—conditions that impair metformin clearance or lactate metabolism. 1, 2, 3
• Nucleoside reverse transcriptase inhibitors (NRTIs), particularly stavudine and didanosine, cause mitochondrial toxicity leading to lactic acidosis with an incidence of approximately 1.3 cases per 1,000 person-years of NRTI exposure. 1 Risk factors include obesity, female sex, prolonged use (>6 months), and pregnancy. 1
• Epinephrine and other beta-agonists elevate lactate through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis independent of tissue perfusion. 2

Organ Dysfunction

• Liver disease impairs lactate clearance since the liver is the major site of lactate removal through gluconeogenesis and oxidation. 1 Hepatic congestion from heart failure can cause elevated lactate. 2
• Renal impairment reduces lactate clearance, with hyperlactatemia reported in 30-65% of adults with chronic kidney disease. 1

Metabolic and Endocrine Causes

• Diabetic ketoacidosis can produce lactic acidosis. 3
• Thiamine deficiency causes pyruvate dehydrogenase dysfunction, impairing lactate metabolism. 1, 3
• Severe hypothyroidism can cause hyperlactatemia. 1

Malignancy and Rare Causes

• Malignancies can cause lactic acidosis through excessive lactate production. 1, 5
• D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon. 1
• Rhabdomyolysis produces lactate as damaged muscle tissue undergoes anaerobic metabolism. 1
• Seizures transiently elevate lactate through intense muscle activity. 6
• Cyanide poisoning blocks oxidative phosphorylation. 5

Mixed and "Cryptic Shock" Scenarios

Up to 23% of septic patients have lactate ≥2 mmol/L with central venous oxygen saturation (ScvO2) >70%, representing "cryptic shock" that doesn't fit traditional definitions. 2 This occurs because sepsis impairs cellular oxygen utilization despite adequate oxygen delivery—low oxygen extraction ratio makes ScvO2 unreliable for directing therapy. 2

Critical Diagnostic Thresholds

• Lactate <2 mmol/L is considered normal. 1, 2, 3
• Lactate 2-4 mmol/L indicates potential tissue hypoperfusion with ~30% mortality. 1, 2
• Lactate ≥4 mmol/L represents a medical emergency with 46.1% mortality, comparable to overt septic shock. 1, 2
• Lactate >5 mmol/L is abnormal and life-threatening. 1, 7
• Lactate >10 mmol/L indicates severe, life-threatening tissue hypoperfusion. 1

Common Pitfalls to Avoid

• Do not dismiss mild lactate elevations (2-4 mmol/L) in seemingly stable patients—this may represent occult tissue hypoperfusion requiring investigation. 1, 2
• Do not assume normal blood pressure excludes tissue hypoperfusion—patients can maintain normal blood pressure through compensatory mechanisms while experiencing significant tissue hypoperfusion. 2
• Do not ignore nonspecific gastrointestinal symptoms (nausea, vomiting, abdominal pain) in at-risk patients taking metformin or NRTIs, as these may be the sole early warning of severe acidosis. 1
• Do not use lactate to diagnose sepsis during labor, as labor itself transiently elevates lactate levels. 2, 3
• Do not assume whole blood and plasma lactate are interchangeable—whole blood measurements are typically 10-15% higher than plasma. 2