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, sepsis, metformin in renal failure, and liver disease impairing lactate clearance.

Type A Lactic Acidosis: Tissue Hypoxia and Hypoperfusion

Type A lactic acidosis occurs when oxygen delivery to tissues is inadequate, forcing cells to rely on anaerobic metabolism and converting pyruvate to lactate to regenerate NAD+ 1.

Circulatory and Cardiovascular Causes

• Shock states of any etiology—hypovolemic, cardiogenic, distributive (septic), or obstructive—impair tissue perfusion and trigger anaerobic glycolysis 2, 1.
• Cardiac failure and severe hypotension lead to inadequate oxygen delivery to tissues 1.
• Acute mesenteric ischemia causes intestinal hypoperfusion, with >88% of patients presenting with metabolic acidosis and elevated lactate 3.
• Hemorrhagic shock following major trauma produces lactate levels that correlate directly with mortality 2.

Respiratory and Hematologic Causes

• Respiratory failure resulting in hypoxemia prevents adequate oxygen delivery 1.
• Severe anemia limits oxygen-carrying capacity 1.

Infection-Related Causes

• Sepsis and septic shock cause both tissue hypoperfusion and inflammatory mediators that affect cellular metabolism 2, 1.
• Severe infections, particularly in patients with underlying conditions like diabetes mellitus, can cause Type A lactic acidosis 3.

Other Type A Causes

• Cyanide poisoning blocks cellular oxygen utilization despite adequate delivery 4.
• Exercise beyond anaerobic threshold when oxygen delivery cannot meet demand 1.

Type B Lactic Acidosis: Metabolic Disturbances Without Hypoxia

Type B lactic acidosis occurs without tissue hypoxia, involving either impaired lactate clearance or increased production from metabolic dysfunction 4, 5.

Medication-Induced Causes

Metformin is the most clinically significant drug cause, with an incidence of 2-9 per 100,000 patients/year 3. Risk dramatically increases with:

• Renal impairment (eGFR <30 mL/min/1.73 m²), as metformin is excreted unchanged in urine 6, 3.
• Acute kidney injury from any cause, which reduces metformin clearance 3.
• Conditions causing anaerobic metabolism: sepsis, hypoxia, shock 3.
• Liver failure, which impairs lactate clearance 3.
• Elderly patients (>65 years) have higher risk 3, 1.

Most episodes of metformin-associated lactic acidosis occur concurrent with acute illness, often when AKI contributes to reduced metformin clearance 6.

Nucleoside reverse transcriptase inhibitors (NRTIs), particularly stavudine and didanosine, cause mitochondrial toxicity by inhibiting DNA polymerase γ 3, 1. The incidence is approximately 1.3 cases per 1,000 person-years of NRTI exposure 3. Risk factors include obesity, female sex, prolonged use (>6 months), and pregnancy 3.

Epinephrine can elevate lactate through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis independent of tissue perfusion 2.

Organ Dysfunction Impairing Lactate Clearance

Liver disease impairs lactate clearance since the liver is the major site of lactate removal through gluconeogenesis and oxidation 3, 1. Under normal conditions, lactate is metabolized by the liver via the Cori cycle 1.

Renal impairment reduces lactate clearance, as kidneys contribute to lactate removal 3. Hyperlactatemia has been reported in 30-65% of adults with chronic kidney disease 3.

Mitochondrial and Metabolic Disorders

Mitochondrial dysfunction can result from:

• NRTI inhibition of DNA polymerase γ, responsible for mitochondrial DNA synthesis 3, 1.
• Thiamine deficiency affecting pyruvate dehydrogenase function 3, 1.
• Mitochondrial DNA point mutations underlying MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) 3.

Inborn errors of metabolism causing Type B lactic acidosis include:

• Organic acidemias: methylmalonic acidemia, propionic acidemia, maple syrup urine disease 3.
• Glycogen storage disease type I with deficient glucose-6-phosphatase activity 3.

Malignancy-Related Causes

Cancer-related metabolic reprogramming (Warburg effect) causes lactate production even with adequate oxygen, as malignant cells preferentially use glycolysis 5. Malignancy was the most common underlying disease accompanied by lactic acidosis in some case series 7.

Other Type B Causes

D-lactic acidosis occurs in patients with short bowel syndrome and preserved colon, where bacterial fermentation produces D-lactate 3, 1.

Rhabdomyolysis causes damaged muscle tissue to undergo anaerobic metabolism, producing lactate 3.

Severe hypothyroidism can cause hyperlactatemia, with hyperprolactinemia reported in 43% of women and 40% of men with frank hypothyroidism 3.

Common Clinical Pitfalls

• Do not ignore metformin-associated lactic acidosis risk in patients with acute illness, even if baseline renal function was adequate—most episodes occur when AKI develops during sepsis, dehydration, or hypoxic states 6.
• Do not dismiss nonspecific gastrointestinal symptoms (nausea, vomiting, abdominal pain) in at-risk patients taking metformin or NRTIs, as these may be the sole early warning of severe acidosis 3.
• Do not overlook mesenteric ischemia when lactate >2 mmol/L is accompanied by abdominal pain, even in hemodynamically stable patients—this combination warrants urgent CT angiography 3.
• Recognize that normal blood pressure does not exclude tissue hypoperfusion in sepsis, as patients can maintain compensatory mechanisms while experiencing significant lactate elevation 2.