What are the type A (hypoxic) and type B (non‑hypoxic) causes of hyperlactatemia?

Hyperlactatemia Causes: Type A (Hypoxic) and Type B (Non-Hypoxic)

Hyperlactatemia is classified into Type A, caused by tissue hypoxia and inadequate oxygen delivery, and Type B, which occurs without tissue hypoxia due to metabolic disturbances, medications, or accelerated aerobic glycolysis. 1

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Type A (Hypoxic) Causes

Type A hyperlactatemia results from inadequate tissue perfusion and oxygen delivery, forcing cells to shift from aerobic to anaerobic metabolism. 2

Circulatory Shock States

• Septic shock is a major cause, driven by both tissue hypoperfusion and inflammatory mediators affecting cellular metabolism, with lactate ≥2 mmol/L defining sepsis-induced tissue hypoperfusion even without hypotension. 1, 2
• Hypovolemic shock from hemorrhage or severe dehydration impairs tissue perfusion and triggers anaerobic glycolysis. 3, 2
• Cardiogenic shock and cardiac failure lead to inadequate cardiac output and tissue oxygen delivery. 1, 2
• Distributive shock from any cause reduces effective circulating volume despite normal or high cardiac output. 2

Tissue Ischemia

• Acute mesenteric ischemia presents with lactate >2 mmol/L in 88% of cases, with levels >2 mmol/L indicating irreversible intestinal ischemia (Hazard Ratio: 4.1). 1, 2
• Arterial embolism to mesenteric or other vascular beds causes sudden lactate elevation and represents a medical emergency. 2

Severe Infections

• Severe sepsis and septic shock, particularly in patients with underlying conditions like diabetes mellitus, cause Type A lactic acidosis through microcirculatory dysfunction. 1

Trauma and Hemorrhage

• Major trauma with hemorrhagic shock leads to elevated lactate levels that correlate directly with mortality; normalization within 24 hours is associated with 100% survival. 2

Respiratory Failure

• Severe hypoxemia from any cause (respiratory failure, severe anemia) impairs oxygen delivery to tissues. 1

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Type B (Non-Hypoxic) Causes

Type B hyperlactatemia occurs without tissue hypoxia, arising from metabolic disturbances, medications, or accelerated aerobic metabolism. 1, 4

Medication-Induced (Type B1)

Metformin

• Metformin-associated lactic acidosis (MALA) occurs with an incidence of 2–9 per 100,000 patients/year, dramatically increasing with renal impairment (eGFR <30 mL/min/1.73 m²). 1, 3
• Risk factors include renal impairment, liver disease, sepsis, hypoxia, acute kidney injury, dehydration, and age >65 years. 1
• Metformin should be discontinued immediately in patients with sepsis, acute kidney injury, or any hypoxic state. 1

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• Stavudine and didanosine cause mitochondrial toxicity leading to lactic acidosis, with an incidence of 1.3 cases per 1,000 person-years of NRTI exposure. 1, 3
• Risk factors include obesity, female sex, prolonged use (>6 months), and pregnancy. 1
• A prodrome of 1–6 weeks with nausea, vomiting, abdominal pain, dyspnea, and weakness often precedes severe acidosis. 1
• Immediate discontinuation of NRTIs is mandatory when lactic acidosis is suspected, as failure to stop carries high mortality. 1

Other Medications

• Epinephrine causes hyperlactatemia through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis independent of tissue perfusion. 1, 2
• Linezolid can precipitate Type B lactic acidosis. 1

Metabolic and Organ Dysfunction (Type B2)

Liver Disease

• Hepatic failure or severe liver dysfunction impairs lactate clearance, as the liver is the major site of lactate removal through gluconeogenesis (Cori cycle). 1, 3
• Hepatic congestion from heart failure can cause cholestatic pattern and elevated lactate. 2

Renal Impairment

• Chronic kidney disease reduces lactate clearance, with hyperlactatemia reported in 30–65% of adult patients. 5, 1

Endocrine Disorders

• Severe primary hypothyroidism can be accompanied by hyperlactatemia, probably due to compensatory thyrotropin-releasing hormone hypersecretion. 5

Inborn Errors of Metabolism (Type B3)

Organic Acidemias

• Methylmalonic acidemia, propionic acidemia, and maple syrup urine disease disrupt normal oxidative metabolism and precipitate Type B lactic acidosis. 1

Mitochondrial Disorders

• MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) results from mitochondrial DNA point mutations impairing oxidative phosphorylation. 1
• MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) presents with episodic lactic acidosis, gastrointestinal dysmotility, and progressive neurological decline, typically manifesting between ages 10–30 years. 1

Glycogen Storage Disease Type I

• GSD I produces chronic hyperlactatemia due to deficient glucose-6-phosphatase activity and impaired gluconeogenesis, presenting with fasting hypoglycemia, hepatomegaly, hypertriglyceridemia, and hyperuricemia. 5, 1

Accelerated Aerobic Glycolysis (Type B2)

Stress-Induced Hyperlactatemia

• Excessive beta-adrenergic stimulation drives accelerated aerobic glycolysis, increasing lactate production without tissue hypoxia—the lactate/pyruvate ratio remains normal (<20) in this circumstance. 1, 4
• Late-onset hyperlactatemia in cardiac surgery patients (arising 6–12 hours post-ICU admission) is a benign, self-limiting condition that spontaneously resolves within 24 hours without evidence of tissue hypoxia. 4

Malignancy

• Warburg effect in malignancies (especially lymphoma) causes lactate elevation through aerobic glycolysis even with adequate tissue oxygenation. 1

D-Lactic Acidosis (Type B3)

• Short bowel syndrome with preserved colon allows bacterial fermentation of carbohydrates, producing D-lactate that is poorly metabolized by humans. 1, 3
• Management requires restricting mono/oligosaccharides, encouraging polysaccharides (starch), thiamine supplementation, and broad-spectrum antibiotics. 1

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Distinguishing Type A from Type B

Clinical Assessment

• Type A presents with signs of hypoperfusion: cold/sweaty extremities, oliguria (<0.5 mL/kg/hr), altered mental status, narrow pulse pressure, and metabolic acidosis (pH <7.35). 2
• Type B often occurs with normal or supranormal hemodynamics, absence of hypoperfusion signs, and may be associated with balanced (normal anion gap) metabolic acidosis and hyperglycemia. 6

Laboratory Differentiation

• Lactate/pyruvate ratio >20 suggests Type A (anaerobic metabolism), while ratio <20 indicates Type B (aerobic glycolysis). 7, 4
• Increased anion gap (Na − [Cl+CO₂] >16) typically accompanies Type A lactic acidosis. 1
• Base deficit from arterial blood gas provides independent information about global tissue acidosis that doesn't strictly correlate with lactate. 2

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Critical Pitfalls to Avoid

• Do not dismiss nonspecific gastrointestinal symptoms (nausea, vomiting, abdominal pain) in at-risk patients taking metformin or NRTIs—these may be the sole early warning of severe acidosis with a 1–6 week prodrome. 1
• Do not ignore elevated lactate in hemodynamically stable patients—up to 23% of septic patients have lactate ≥2 mmol/L with normal ScvO₂ >70%, representing "cryptic shock." 1, 2
• Do not assume normal blood pressure excludes tissue hypoperfusion—patients can maintain MAP through compensatory mechanisms while experiencing significant tissue hypoxia. 2
• Do not overlook mesenteric ischemia when lactate >2 mmol/L with abdominal pain—proceed urgently to CT angiography, as diagnostic delay is the dominant factor in 30–70% mortality. 1, 2