What are the causes of lactic acidosis?

Causes of Lactic Acidosis

Lactic acidosis results from either excessive lactate production (Type A) due to tissue hypoxia or impaired lactate clearance/mitochondrial dysfunction (Type B), with the most critical causes being circulatory shock, severe infections, 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 Cardiovascular Causes

• Shock states (cardiogenic, hypovolemic, obstructive, or distributive) cause inadequate tissue perfusion and are the most common cause of Type A lactic acidosis 2, 1
• Cardiac failure and severe hypotension lead to insufficient oxygen delivery to tissues 1
• Acute mesenteric ischemia causes intestinal hypoperfusion and should be suspected when lactic acidosis occurs with abdominal pain and elevated urea (88% of patients present with metabolic acidosis) 2
• Acute myocardial infarction and cardiovascular collapse are associated with lactic acidosis and prerenal azotemia 3

Infection and Sepsis

• Severe infections and sepsis cause tissue hypoperfusion combined with increased metabolic demands, particularly in patients with underlying conditions like diabetes 2, 1
• Sepsis-related lactic acidosis requires aggressive treatment including source control, antibiotics within 3 hours, and hemodynamic support 2

Respiratory and Hematologic Causes

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

Type B Lactic Acidosis: Impaired Clearance and Metabolic Dysfunction

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

Medication-Induced Causes

Metformin is the most clinically significant drug cause, with an 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
• Risk factors include: renal impairment (most critical), age ≥65 years, liver disease, heart failure, acute illness, dehydration, and excessive alcohol intake 3
• Must be discontinued during acute illness with hemodynamic instability, before contrast procedures (in at-risk patients), and during surgical procedures requiring NPO status 2, 3

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) cause mitochondrial toxicity by inhibiting DNA polymerase γ 2, 1:

• Stavudine and didanosine carry the highest risk (incidence 1.3 cases/1,000 person-years) 2
• Risk factors include obesity, female sex, prolonged use >6 months, and pregnancy 2
• Requires immediate discontinuation when lactic acidosis develops 2

Organ Dysfunction

Liver disease is a critical cause because the liver is the major site of lactate removal through gluconeogenesis and oxidation 2, 5, 6:

• Impaired lactate clearance results in higher blood lactate levels 3
• 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, 5:

• Hyperlactatemia occurs in 30-65% of adults with chronic kidney disease 2
• Metformin accumulation dramatically increases risk with declining renal function 2, 3

Metabolic and Mitochondrial Disorders

• Thiamine deficiency affects pyruvate dehydrogenase function, leading to mitochondrial dysfunction 2, 1
• D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon due to bacterial fermentation of carbohydrates 2
• Severe hypothyroidism can cause hyperlactatemia 2
• Organic acidemias (methylmalonic acidemia, propionic acidemia, maple syrup urine disease) are inborn errors of metabolism 2

Other Important Causes

• Malignancies can cause lactate overproduction 5
• Cyanide poisoning disrupts cellular oxygen utilization 5
• Rhabdomyolysis causes damaged muscle tissue to undergo anaerobic metabolism, producing lactate 2
• Malignant hyperthermia increases metabolic rate and muscle contractile activity 2

Critical Clinical Pitfalls

Do not ignore subtle early symptoms such as nonspecific gastrointestinal complaints (nausea, vomiting, abdominal pain), dyspnea, generalized weakness, and myalgias—these often precede severe acidosis 2, 3.

Mesenteric ischemia must be considered urgently when lactic acidosis presents with abdominal pain and elevated urea; lactate >2 mmol/L is associated with irreversible intestinal ischemia (HR 4.1), and diagnostic delay is the dominant factor in mortality (30-70%) 2.

Metformin-associated lactic acidosis is characterized by blood lactate >5 mmol/L, anion gap acidosis, increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL 3. Hemodialysis is the definitive treatment and often reverses symptoms 2, 3.

In COVID-19 patients with type 2 diabetes, metformin use was associated with significantly increased lactic acidosis incidence (adjusted HR 4.46) 2.

Alcohol potentiates metformin's effect on lactate metabolism and should be avoided 3.