What are the causes of lactic acidosis?

Causes of Lactic Acidosis

Lactic acidosis results from either tissue hypoxia (Type A) or metabolic disturbances without hypoxia (Type B), with the most critical causes being circulatory shock, sepsis, metformin toxicity in renal impairment, and liver disease.

Type A Lactic Acidosis: Tissue Hypoxia and Hypoperfusion

Type A lactic acidosis occurs when oxygen delivery cannot meet tissue metabolic demands, forcing cells into anaerobic metabolism where pyruvate converts to lactate to regenerate NAD+ 1.

Circulatory and Cardiac Causes

• Shock states (cardiogenic, septic, hypovolemic, or obstructive) cause inadequate tissue perfusion and are the most common triggers 2, 1
• Cardiac failure and severe hypotension lead to insufficient oxygen delivery to tissues 1
• Acute myocardial infarction and cardiovascular collapse create hypoxic conditions 3

Infection and Sepsis

• Severe infections and sepsis cause both tissue hypoperfusion and increased metabolic demands 1
• Sepsis-related lactic acidosis requires aggressive treatment with source control, antibiotics within 3 hours, and hemodynamic support 2

Mesenteric and Vascular Ischemia

• Acute mesenteric ischemia causes lactic acidosis from intestinal hypoperfusion, with 88% of patients presenting with metabolic acidosis 2, 1
• Lactate >2 mmol/L combined with abdominal pain and elevated urea strongly suggests mesenteric ischemia and requires immediate CT angiography 2
• Risk factors include atrial fibrillation, recent myocardial infarction, cardiac failure, and diffuse atherosclerotic disease 1

Respiratory and Hematologic Causes

• Respiratory failure with hypoxemia impairs oxygen delivery 1
• Severe anemia limits oxygen-carrying capacity 1
• Exercise beyond anaerobic threshold when oxygen delivery is insufficient 1

Rhabdomyolysis

• Damaged muscle tissue undergoes anaerobic metabolism during rhabdomyolysis, producing lactate 2
• Severe cases progress to metabolic crisis with lactic acidosis, hyperkalemia, and hypocalcemia 2

Type B Lactic Acidosis: Metabolic Dysfunction Without Hypoxia

Type B lactic acidosis occurs from impaired lactate clearance or mitochondrial dysfunction without tissue hypoxia 4, 5.

Medication-Induced Causes

Metformin is the most clinically significant drug cause, with incidence of 2-9 per 100,000 patients/year 2. The FDA mandates specific precautions 3:

• Contraindicated when eGFR <30 mL/min/1.73 m² 3
• Not recommended for initiation when eGFR 30-45 mL/min/1.73 m² 3
• Stop metformin immediately in patients with sepsis, acute kidney injury, hypoxic states (acute heart failure, shock, myocardial infarction), before contrast procedures (eGFR 30-60), and during surgical procedures requiring NPO status 3
• Elderly patients (≥65 years) have higher risk due to greater likelihood of hepatic, renal, or cardiac impairment 3
• Excessive alcohol intake potentiates metformin's effect on lactate metabolism 3

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) used in HIV treatment cause mitochondrial toxicity 2:

• Stavudine and didanosine are highest risk, with incidence of 1.3 cases/1,000 person-years of NRTI exposure 2
• Risk factors include obesity, female sex, prolonged use (>6 months), and pregnancy 2
• Mitochondrial dysfunction occurs from inhibition of DNA polymerase γ 2, 1
• Discontinue NRTIs immediately when lactic acidosis develops due to high mortality without intervention 2

Organ Dysfunction

Liver disease is a critical cause because the liver is the major site of lactate removal through gluconeogenesis and oxidation 2, 6:

• Impaired lactate clearance results in higher blood lactate levels 2
• Metformin should be avoided in patients with clinical or laboratory evidence of hepatic disease 3

Renal impairment reduces lactate clearance as kidneys contribute to lactate removal 2, 4:

• Chronic kidney disease patients have 30-65% incidence of hyperlactatemia 2
• Risk of metformin accumulation increases dramatically with declining renal function 3

Metabolic and Nutritional Deficiencies

Thiamine deficiency affects pyruvate dehydrogenase function, causing mitochondrial dysfunction 2, 1, 7:

• Can occur in malignancy, alcoholism, and malnutrition 7
• Treatment includes thiamine supplementation 2

D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon 2, 1:

• Produced by intestinal microbiota from carbohydrate fermentation 2
• Management requires restricting mono/oligosaccharides, encouraging polysaccharides, thiamine supplements, and broad-spectrum antibiotics 2

Other Type B Causes

• Malignancies, particularly hematologic malignancies 8, 5
• Cyanide poisoning 4
• Grand mal seizures 5
• Diabetic ketoacidosis can present with concurrent type B lactic acidosis 5
• Severe hypothyroidism 2
• Congenital enzyme deficiencies including methylmalonic acidemia, propionic acidemia, and maple syrup urine disease 2

Diagnostic Thresholds

Laboratory criteria for lactic acidosis 2, 1:

• Lactate >2 mmol/L: Elevated, criterion for severe sepsis
• Lactate >5 mmol/L: Abnormal, characteristic of lactic acidosis
• Lactate >10 mmol/L: Serious/life-threatening
• Arterial pH <7.35: Acidosis
• Increased anion gap >16: Characteristic finding

Critical Clinical Pitfalls

Never ignore hyperlactatemia even without hypotension, as it may indicate occult tissue hypoperfusion or organ dysfunction 2. In patients with lactate elevation, abdominal pain, and elevated urea, immediately consider mesenteric ischemia—diagnostic delay is the dominant factor in 30-70% mortality 2. Do not use lactate to diagnose sepsis during labor, as labor itself elevates lactate levels 2. Proper lactate measurement requires prechilled fluoride-oxalate tubes, transport on ice, processing within 4 hours, and collection without tourniquet or fist-clenching 2.