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 common causes being circulatory shock, severe infections, metformin use in renal impairment, and liver disease. 1

Type A Lactic Acidosis (Tissue Hypoxia)

Type A lactic acidosis occurs when tissues cannot receive adequate oxygen, forcing cells into anaerobic metabolism that produces excess lactate. 1

Circulatory Causes

• Shock states (cardiogenic, hypovolemic, obstructive) cause inadequate tissue perfusion and are the most common cause of Type A lactic acidosis 1, 2
• Cardiac failure leads to insufficient oxygen delivery to tissues 1, 3
• Acute mesenteric ischemia presents with the combination of lactic acidosis, elevated urea, and abdominal pain—88% of these patients have metabolic acidosis with elevated lactate 1
• Severe hypotension from any cause reduces tissue perfusion 3

Infection-Related

• Severe infections and sepsis cause both tissue hypoperfusion and increased metabolic demands, particularly dangerous in patients with underlying diabetes mellitus 1, 2

Respiratory and Hematologic

• Respiratory failure with hypoxemia limits oxygen availability 3
• Severe anemia reduces oxygen-carrying capacity 3

Other Type A Causes

• Rhabdomyolysis causes damaged muscle tissue to undergo anaerobic metabolism, producing lactate—particularly concerning in sickle cell trait patients with exertional rhabdomyolysis 1
• Exercise beyond anaerobic threshold when oxygen delivery cannot meet demand 3

Type B Lactic Acidosis (Without Tissue Hypoxia)

Type B lactic acidosis occurs due to metabolic disturbances, drug toxicity, or impaired lactate clearance without primary tissue hypoxia. 1

Medication-Induced

Metformin is the most clinically significant drug cause:

• Incidence of 2-9 per 100,000 patients per year, primarily in patients with significant renal impairment 1, 4
• Contraindicated when eGFR <30 mL/min/1.73m² 4
• Initiation not recommended when eGFR 30-45 mL/min/1.73m² 4
• Risk factors include: renal impairment, liver disease, age >65 years, congestive heart failure, and acute illness 1, 4
• Must be discontinued before iodinated contrast procedures in patients with eGFR 30-60 mL/min/1.73m² 4

Nucleoside Reverse Transcriptase Inhibitors (NRTIs):

• Stavudine and didanosine cause mitochondrial toxicity by inhibiting DNA polymerase γ 1, 2
• Incidence approximately 1.3 cases per 1,000 person-years of NRTI exposure 1
• Risk factors: obesity, female sex, prolonged use (>6 months), pregnancy 1
• Incidence has decreased as newer antiretrovirals replaced older NRTIs 1

Organ Dysfunction

Liver disease is a critical cause:

• Impairs lactate clearance since the liver normally metabolizes lactate 1, 3
• Patients with hepatic impairment should avoid metformin 4

Renal impairment:

• Reduces lactate clearance and increases risk of drug accumulation 1
• eGFR <30 mL/min/1.73m² dramatically increases risk 1, 4

Metabolic and Nutritional

• Thiamine deficiency affects pyruvate dehydrogenase function, causing mitochondrial dysfunction 1, 3
• D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon due to bacterial fermentation 1, 2
• Inborn errors of metabolism including methylmalonic acidemia, propionic acidemia, and maple syrup urine disease 1

Toxins and Other Causes

• Excessive alcohol intake potentiates metformin's effect on lactate metabolism 4
• Cyanide poisoning disrupts cellular respiration 5
• Certain malignancies increase lactate production 5
• Malignant hyperthermia increases metabolic rate and muscle contractile activity 1

Critical Clinical Pitfalls

Do not ignore subtle early symptoms: Nonspecific gastrointestinal symptoms (nausea, vomiting, abdominal pain), dyspnea, generalized weakness, and myalgias often precede severe acidosis and should prompt immediate evaluation. 1

Mesenteric ischemia warning: The combination of lactic acidosis with elevated urea and abdominal pain strongly suggests acute mesenteric ischemia—lactate >2 mmol/L is associated with irreversible intestinal ischemia (HR 4.1). This requires immediate CT angiography without delay, as diagnostic delay is the dominant factor in mortality (30-70%). 1

Multiple causes often coexist: In any given patient with lactic acidosis, several contributing factors may be present simultaneously, requiring comprehensive evaluation. 6

Hyperlactatemia without hypotension: Lactate ≥2 mmol/L indicates sepsis severity even with normal blood pressure and represents occult tissue hypoperfusion requiring aggressive treatment. 1