What are the classifications of lactic acidosis, including Type A and Type B?

Classification of Lactic Acidosis

Lactic acidosis is classified into two major types based on pathophysiology: Type A results from tissue hypoxia and hypoperfusion, while Type B occurs without tissue hypoxia due to metabolic disturbances, drug toxicity, or malignancy. 1, 2, 3

Type A Lactic Acidosis (Tissue Hypoxia/Hypoperfusion)

Type A lactic acidosis develops when tissues cannot receive adequate oxygen, forcing cells to regenerate ATP through anaerobic metabolism rather than oxidative phosphorylation. 1, 4

Primary Causes

• Circulatory disorders including all forms of shock (hypovolemic, cardiogenic, distributive, obstructive) lead to inadequate tissue perfusion and oxygen delivery. 1, 5
• Sepsis and septic shock cause lactic acidosis through both tissue hypoperfusion and inflammatory mediators that disrupt cellular metabolism. 5
• Severe infections, particularly in patients with underlying conditions like diabetes mellitus, can precipitate Type A lactic acidosis. 1
• Hemorrhagic shock and major trauma produce lactate levels that correlate directly with mortality. 5
• Cardiac failure and myocardial infarction impair cardiac output and tissue oxygen delivery. 6
• Pulmonary disorders that compromise oxygen transfer can trigger Type A lactic acidosis. 4

Pathophysiology

When oxygen delivery is insufficient, cells shift from aerobic metabolism (oxidative phosphorylation) to anaerobic glycolysis, producing lactate as the end product. 1, 4 This occurs because pyruvate cannot enter the mitochondrial Krebs cycle without adequate oxygen, so it is converted to lactate instead. 4

Type B Lactic Acidosis (Without Tissue Hypoxia)

Type B lactic acidosis occurs when tissue oxygenation is maintained but metabolic disturbances cause lactate accumulation. 1, 3, 7 This category is subdivided based on etiology:

Type B1: Underlying Diseases

• Malignancy-associated lactic acidosis occurs through the Warburg effect, where cancer cells preferentially use anaerobic glycolysis even in the presence of oxygen. 2, 8 This is particularly common with hematologic malignancies like diffuse large B-cell lymphoma. 2, 8
• Liver disease impairs lactate clearance since the liver is the major site of lactate removal through gluconeogenesis and oxidation. 1, 6
• Renal impairment reduces lactate clearance, with hyperlactatemia reported in 30-65% of adults with chronic kidney disease. 1
• Severe hypothyroidism can cause hyperlactatemia. 1
• Thiamine deficiency (pyruvate dehydrogenase dysfunction) prevents lactate conversion to acetyl-CoA. 1, 4

Type B2: Medications and Toxins

• Metformin causes lactic acidosis when clearance is impaired (eGFR <30 mL/min/1.73 m²) or in conditions causing anaerobic metabolism (sepsis, hypoxia), with an incidence of 2-9 per 100,000 patients/year. 1, 6
• Nucleoside reverse transcriptase inhibitors (NRTIs), particularly stavudine and didanosine, cause mitochondrial toxicity leading to lactic acidosis with an incidence of approximately 1.3 cases per 1,000 person-years of NRTI exposure. 1
• Albuterol can induce Type B lactic acidosis through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis independent of tissue perfusion. 5, 3
• Epinephrine elevates lactate through beta-2-adrenergic stimulation, increasing lactate production without tissue hypoxia. 5

Type B3: Inborn Errors of Metabolism

• Organic acidemias including methylmalonic acidemia, propionic acidemia, and maple syrup urine disease are inborn errors of metabolism that cause Type B lactic acidosis. 9, 1
• Mitochondrial disorders such as MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome) result from point mutations in mitochondrial DNA. 9
• Glycogen storage disease Type I presents with hyperlactatemia due to impaired glucose-6-phosphatase function. 9

Mixed Type A and Type B Lactic Acidosis

Both types can co-occur in critically ill patients, making diagnosis and management particularly challenging. 8 For example, a patient with septic shock (Type A) and underlying lymphoma (Type B) may have refractory lactic acidosis that only resolves when both conditions are addressed. 8

Diagnostic Thresholds

• Lactate >2 mmol/L indicates potential tissue hypoperfusion and warrants investigation. 1, 5
• Lactate >5 mmol/L is abnormal and requires urgent evaluation. 1, 7
• Lactate >10 mmol/L is life-threatening and indicates severe tissue hypoperfusion regardless of cause. 1
• Arterial pH <7.35 with elevated lactate defines lactic acidosis, though concomitant alkalosis may mask the acidemia. 1, 7
• Increased anion gap (>16) typically accompanies lactic acidosis but may be masked by hypoalbuminemia. 1, 7

Critical Distinction for Management

Differentiating Type A from Type B is crucial because treatment strategies differ fundamentally. 2, 3 Type A requires aggressive resuscitation to restore tissue perfusion, while Type B requires identifying and treating the underlying metabolic disturbance or discontinuing offending medications. 1, 3 In Type A, lactate elevation reflects inadequate oxygen delivery; in Type B, it reflects abnormal cellular metabolism despite adequate oxygenation. 2, 7