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 critical causes being circulatory shock, sepsis, metformin in renal impairment, liver disease, and certain medications—particularly nucleoside reverse transcriptase inhibitors (NRTIs).

Type A Lactic Acidosis: Tissue Hypoxia and Hypoperfusion

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

Circulatory and Shock States

• Shock states (hypovolemic, cardiogenic, distributive, and obstructive) cause inadequate tissue perfusion and are the most common cause of elevated lactate 1, 2
• Sepsis and septic shock lead to lactic acidosis through both tissue hypoperfusion and inflammatory mediators affecting cellular metabolism 1, 2
• Cardiac failure and cardiovascular collapse result in inadequate oxygen delivery to tissues 1, 3
• Acute myocardial infarction causes tissue hypoxia and prerenal azotemia 4

Hemorrhage and Trauma

• Hemorrhagic shock following major trauma produces elevated lactate levels that correlate directly with mortality 2
• Trauma with significant blood loss creates oxygen debt requiring aggressive resuscitation 1

Mesenteric and Vascular Ischemia

• Acute mesenteric ischemia (particularly embolic occlusion of the superior mesenteric artery) presents with lactate >2 mmol/L indicating irreversible intestinal ischemia (Hazard Ratio: 4.1) 1
• More than 88% of patients with mesenteric ischemia present with metabolic acidosis and elevated lactate 1
• Arterial embolism to mesenteric vessels causes sudden lactate elevation, typically in patients with atrial fibrillation 1

Respiratory and Hypoxic States

• Acute congestive heart failure (particularly with hypoperfusion and hypoxemia) is a common setting for metformin-associated lactic acidosis 4
• Chronic pulmonary disease with acute decompensation requires monitoring for lactic acidosis 1
• Conditions associated with hypoxemia cause prerenal azotemia and lactic acidosis 4

Type B Lactic Acidosis: Metabolic and Drug-Induced

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

Medication-Induced Causes

Metformin

• Metformin is the most clinically significant drug cause of lactic acidosis, with an incidence of 2-9 per 100,000 patients/year 1, 3
• The FDA mandates metformin is contraindicated when eGFR <30 mL/min/1.73 m² and should not be initiated in patients with eGFR 30-45 mL/min/1.73 m² 4
• Metformin decreases liver uptake of lactate, increasing blood lactate levels, and inhibits mitochondrial respiration in a concentration-dependent manner 4, 5
• Risk dramatically increases with renal impairment because metformin is substantially excreted by the kidney 1, 4
• Metformin-associated lactic acidosis is characterized by blood lactate >5 mmol/L, anion gap acidosis without ketonuria, increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL 4

Critical Risk Factors for Metformin-Associated Lactic Acidosis

• Age ≥65 years increases risk due to greater likelihood of hepatic, renal, or cardiac impairment 1, 4
• Acute illness requiring hospitalization including sepsis, acute kidney injury, or hypoxic states mandates immediate metformin discontinuation 1, 4
• Radiologic contrast procedures require stopping metformin in patients with eGFR 30-60 mL/min/1.73 m², hepatic impairment, alcoholism, heart failure, or intra-arterial contrast administration 4
• Surgery and NPO status with volume depletion, hypotension, and renal impairment necessitate temporary discontinuation 4
• Excessive alcohol intake potentiates metformin's effect on lactate metabolism 4

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• Stavudine and didanosine (older NRTIs used in HIV treatment) cause mitochondrial toxicity by inhibiting DNA polymerase γ, with an incidence of approximately 1.3 cases per 1,000 person-years of NRTI exposure 1, 3
• Risk factors for NRTI-induced lactic acidosis include obesity, female sex, prolonged use (>6 months), and pregnancy 1
• The incidence has decreased as newer antiretrovirals have replaced older NRTIs 1

Other Medications

• Epinephrine causes elevated lactate through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis independent of tissue perfusion 2

Organ Dysfunction and Impaired Lactate Clearance

Liver Disease

• Hepatic impairment reduces lactate clearance since the liver is the major site of lactate removal through gluconeogenesis and oxidation 1, 4
• Patients with clinical or laboratory evidence of hepatic disease should avoid metformin 4

Renal Impairment

• Chronic kidney disease reduces lactate clearance, with hyperlactatemia reported in 30-65% of adults with chronic renal disease 1
• Renal dysfunction is a critical risk factor for metformin accumulation and lactic acidosis 1, 4

Metabolic and Endocrine Causes

• Severe primary hypothyroidism can cause hyperlactatemia 1
• Tetrahydrobiopterin deficiency causes hyperlactatemia in up to 80% of affected patients 1
• Thiamine (pyruvate dehydrogenase) deficiency impairs lactate metabolism 1, 6

Infection and Sepsis

• Severe infections, particularly in patients with underlying conditions like diabetes mellitus, cause Type A lactic acidosis 1, 3
• Sepsis creates both tissue hypoperfusion and inflammatory-mediated cellular metabolic dysfunction 2

Malignancy and Rhabdomyolysis

• Certain malignancies can cause lactic acid overproduction 1, 6
• Rhabdomyolysis causes damaged muscle tissue to undergo anaerobic metabolism, producing lactate 1
• Malignant hyperthermia leads to increased metabolic rate and muscle contractile activity, resulting in lactic acidosis 1

Special Gastrointestinal Causes

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

Critical Clinical Pitfalls

• Do not ignore elevated lactate in seemingly stable patients, as it may indicate occult tissue hypoperfusion even with normal blood pressure 1, 2
• Do not rely on blood pressure alone to assess tissue perfusion in sepsis—patients can maintain normal blood pressure through compensatory mechanisms while experiencing significant hypoperfusion 1
• Do not delay imaging for suspected mesenteric ischemia—when lactate >2 mmol/L with abdominal pain, proceed urgently to CT angiography as diagnostic delay is the dominant factor in mortality (30-70%) 1
• Do not use lactate to diagnose sepsis during labor, as labor itself transiently elevates lactate levels 1
• Subtle early symptoms (nonspecific gastrointestinal symptoms, dyspnea, generalized weakness, myalgias) often precede severe acidosis and should not be ignored 1, 3