What causes lactic acidosis?

Lactic Acidosis Causes

Lactic acidosis results from either tissue hypoxia causing excessive lactate production (Type A) or metabolic disturbances causing impaired lactate clearance without hypoxia (Type B), with circulatory shock, severe infections, and medication toxicity being the most common culprits in clinical practice. 1, 2

Type A Lactic Acidosis: Tissue Hypoxia-Related Causes

Type A lactic acidosis occurs when tissues cannot receive adequate oxygen, forcing cells into anaerobic metabolism that produces lactate to regenerate ATP. 2

Circulatory Disorders

• Shock states (cardiogenic, hypovolemic, septic, or obstructive) cause inadequate tissue perfusion and are the most common cause of Type A lactic acidosis 1, 2
• Cardiac failure limits oxygen delivery to tissues 1, 2
• Severe hypotension compromises perfusion 2

Tissue Perfusion Compromise

• Acute mesenteric ischemia causes intestinal hypoperfusion; 88% of patients present with metabolic acidosis and elevated lactate 1
• Severe infections and sepsis increase metabolic demands while compromising tissue perfusion 1, 2
• Respiratory failure resulting in hypoxemia 2
• Severe anemia limiting oxygen-carrying capacity 2

Other Type A Causes

• Exercise beyond anaerobic threshold when oxygen delivery cannot meet demand 2
• Rhabdomyolysis causes damaged muscle tissue to undergo anaerobic metabolism, producing lactate 1

Type B Lactic Acidosis: Non-Hypoxic Causes

Type B lactic acidosis occurs without tissue hypoxia, typically from impaired lactate clearance or metabolic disturbances. 1, 2

Medication-Induced Causes

Metformin is the most clinically significant drug cause:

• Incidence of 2-9 per 100,000 patients/year 1
• Risk dramatically increases with renal impairment because metformin is renally cleared 3, 4
• The FDA mandates metformin should not be used in men with serum creatinine ≥1.5 mg/dL or women with ≥1.4 mg/dL 3
• Contraindicated when eGFR <30 mL/min/1.73 m² 4
• Initiation not recommended when eGFR 30-45 mL/min/1.73 m² 4
• Risk factors include elderly patients (>65 years), liver disease, congestive heart failure, and acute illness 1, 4

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) used in HIV treatment:

• Particularly stavudine and didanosine cause mitochondrial toxicity by inhibiting DNA polymerase γ 1, 5
• Incidence 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

Metabolic and Organ Dysfunction

Liver disease impairs lactate clearance since the liver is the major site of lactate removal through gluconeogenesis and oxidation. 3, 4, 6

Thiamine deficiency affects pyruvate dehydrogenase function, causing mitochondrial dysfunction and impaired lactate metabolism. 1, 2

Renal impairment reduces lactate clearance as kidneys contribute to lactate removal. 3, 6

Special Metabolic Conditions

D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon, where colonic bacteria produce D-lactate from unabsorbed carbohydrates. 1

Inborn errors of metabolism including methylmalonic acidemia, propionic acidemia, and maple syrup urine disease can cause Type B lactic acidosis. 1

Malignancy

Cancer can cause lactic acidosis through increased anaerobic metabolism in tumor cells; lactate may act as a "signal molecule" promoting angiogenesis and tumor progression. 1, 7

Critical Clinical Context

High-Risk Scenarios Requiring Immediate Evaluation

When lactate >2 mmol/L occurs with abdominal pain and elevated urea, strongly suspect acute mesenteric ischemia—this combination demands immediate CT angiography as diagnostic delay is the dominant mortality factor (30-70% mortality). 1

In patients with COVID-19 and diabetes on metformin, the risk of lactic acidosis increases substantially (adjusted hazard ratio 4.46). 1

Common Pitfalls to Avoid

Do not ignore hyperlactatemia (≥2 mmol/L) even without hypotension—it indicates tissue hypoperfusion and meets criteria for severe sepsis; persistent elevation despite normal blood pressure suggests occult organ dysfunction. 1

Alcohol potentiates metformin's effect on lactate metabolism; patients should be warned against excessive alcohol intake while receiving metformin. 4

Withhold metformin before iodinated contrast procedures in patients with eGFR 30-60 mL/min/1.73 m², history of liver disease, alcoholism, heart failure, or when intra-arterial contrast will be used; restart only after confirming stable renal function at 48 hours. 4