What are the causes of lactic acidosis?

Causes of Lactic Acidosis

Lactic acidosis results from either tissue hypoxia (Type A) or metabolic dysfunction without hypoxia (Type B), with the most common causes being circulatory shock, severe infections, metformin in renal impairment, and mitochondrial toxins.

Type A Lactic Acidosis: Tissue Hypoxia

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

• Circulatory shock (cardiogenic, hypovolemic, obstructive) causes inadequate tissue perfusion and is the most common cause 1, 2
• Severe infections and sepsis, particularly in patients with underlying conditions like diabetes mellitus 1, 2
• Acute congestive heart failure, especially when accompanied by hypoperfusion and hypoxemia 3
• Cardiovascular collapse, acute myocardial infarction, and conditions associated with hypoxemia 3
• Respiratory failure leading to inadequate oxygen delivery 1

Type B Lactic Acidosis: Non-Hypoxic Causes

Type B lactic acidosis occurs despite adequate tissue oxygenation, typically from metabolic dysfunction or toxins:

Medication-Induced Causes

• Metformin is the most important drug cause, with an incidence of 2-9/100,000 patients/year, particularly dangerous in renal impairment (eGFR <30 mL/min/1.73m²) 1, 3

  • Metformin decreases hepatic lactate uptake and inhibits mitochondrial respiration, increasing blood lactate levels 3, 4
  • Risk factors include: renal impairment, liver disease, age >65 years, congestive heart failure, and excessive alcohol intake 3
  • Metformin plasma levels >5 mcg/mL are typically associated with lactic acidosis 3

• Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV treatment, especially stavudine and didanosine, cause mitochondrial toxicity 5, 1, 2

  • NRTIs inhibit DNA polymerase γ, the enzyme responsible for mitochondrial DNA synthesis 5, 1
  • Estimated incidence: 1.3 cases/1000 person-years of NRTI exposure 5
  • Risk factors: obesity, female sex, prolonged NRTI use, pregnancy (particularly late stages or postpartum) 5

• Aminoglycosides (e.g., neomycin) can cause lactic acidosis through mitochondrial toxicity, inhibiting cellular respiration even with adequate oxygen 6

Metabolic and Organ Dysfunction

• Liver disease impairs lactate clearance, as the liver normally removes lactate through oxidation or conversion to glucose 1, 2, 3, 7
• Thiamine (vitamin B1) deficiency causes pyruvate dehydrogenase dysfunction, preventing lactate metabolism 1, 7
• D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon, where colonic bacteria produce D-lactate from carbohydrate fermentation 1

Other Causes

• Malignancies, particularly hematologic malignancies, can cause lactate overproduction 7
• Cyanide poisoning blocks oxidative phosphorylation 7
• Rhabdomyolysis causes damaged muscle tissue to undergo anaerobic metabolism, producing lactate 1

Critical Risk Factors and Clinical Context

Several conditions dramatically increase the risk of lactic acidosis:

• Renal impairment is the single most important risk factor for metformin-associated lactic acidosis, as metformin is substantially excreted by the kidneys 3
• Contrast dye administration in metformin-treated patients can cause acute renal function decline 3
• Surgery and procedures with restricted food/fluid intake increase risk through volume depletion and hypotension 3
• Excessive alcohol intake potentiates metformin's effect on lactate metabolism 3

Common Clinical Pitfalls

Avoid these critical errors when evaluating lactic acidosis:

• Do not assume all lactic acidosis is Type A (hypoxic) - persistent lactic acidosis despite adequate fluid resuscitation and tissue perfusion suggests Type B causes, particularly medications 6
• Do not continue metformin in patients with eGFR <30 mL/min/1.73m² - this is an absolute contraindication 3
• Do not ignore subtle early symptoms - nonspecific gastrointestinal symptoms (nausea, vomiting, abdominal pain), dyspnea, generalized weakness, and myalgias often precede severe acidosis 5, 1, 2
• Do not delay discontinuation of offending agents while pursuing other causes - immediately stop suspected causative medications 1, 6
• Do not use standard lactate collection techniques - proper measurement requires prechilled fluoride-oxalate tubes, immediate transport on ice, processing within 4 hours, and collection without tourniquet or fist-clenching 1, 2