What are the causes of elevated lactate?

Causes of Elevated Lactate

Elevated lactate results primarily from tissue hypoperfusion and hypoxia causing anaerobic metabolism, though numerous other mechanisms including medication effects, impaired clearance, and accelerated aerobic glycolysis can also raise lactate levels independent of tissue oxygenation. 1

Primary Mechanisms of Lactate Elevation

Type A: Tissue Hypoperfusion and Hypoxia

Inadequate oxygen delivery to tissues is the most common cause of elevated lactate, forcing cells to rely on anaerobic glycolysis for ATP production. 1, 2 This occurs across multiple shock states:

• Sepsis and septic shock cause lactic acidosis through both tissue hypoperfusion and inflammatory mediators that disrupt cellular metabolism at the mitochondrial level. 1
• Hypovolemic, cardiogenic, and distributive shock all impair tissue perfusion through different mechanisms but share the common pathway of inadequate oxygen delivery. 1
• Hemorrhagic shock and major trauma produce lactate elevations that correlate directly with mortality risk. 1

Type B: Elevated Lactate Without Tissue Hypoxia

Lactate can rise substantially even when tissue oxygenation remains adequate, through several distinct pathways:

• Accelerated aerobic glycolysis driven by excess beta-adrenergic stimulation increases lactate production independent of tissue perfusion. 1
• Impaired lactate clearance occurs with liver disease or hepatic hypoperfusion, since the liver is the primary site for lactate removal through gluconeogenesis. 1, 3
• Mitochondrial dysfunction prevents pyruvate oxidation even when oxygen is available, forcing continued lactate production. 4, 3

Medication-Induced Causes

Beta-Adrenergic Agents

Epinephrine causes elevated lactate through beta-2-adrenergic receptor stimulation in skeletal muscle, activating glycogenolysis and glycolysis that increase lactate production completely independent of tissue perfusion status. 1 This represents a critical pitfall—patients on vasopressors may have elevated lactate from the medication itself rather than inadequate resuscitation.

Metformin

Metformin causes lactic acidosis specifically in patients with impaired clearance (renal failure with eGFR <30 mL/min/1.73 m²), impaired lactate clearance (liver failure), or conditions causing anaerobic metabolism (sepsis, hypoxia). 1, 5 The incidence is 2-9 per 100,000 patients per year, but risk increases dramatically with renal impairment. 5

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

NRTIs, particularly stavudine and didanosine, cause mitochondrial toxicity by inhibiting DNA polymerase γ responsible for mitochondrial DNA synthesis. 5 The incidence is approximately 1.3 cases per 1,000 person-years of NRTI exposure, with higher risk in obese patients, females, and during pregnancy. 5

Organ-Specific Causes

Mesenteric Ischemia

Acute mesenteric ischemia presents with elevated lactate >2 mmol/L, which indicates irreversible intestinal ischemia with a hazard ratio of 4.1. 1 More than 88% of patients with mesenteric ischemia present with metabolic acidosis and elevated lactate. 1 This represents a surgical emergency where lactate elevation combined with abdominal pain warrants immediate CT angiography, even in hemodynamically stable patients. 1

Liver Dysfunction

Hepatic disease impairs lactate clearance since the liver removes lactate through gluconeogenesis and oxidation (Cori cycle). 5, 3 Hepatic congestion from heart failure can cause both cholestatic patterns and elevated lactate. 5

Renal Impairment

Kidney dysfunction reduces lactate clearance as the kidneys contribute to lactate removal, with hyperlactatemia reported in 30-65% of adults with chronic kidney disease. 5, 3

Metabolic and Endocrine Causes

• Diabetic ketoacidosis can cause elevated lactate levels. 6
• Thiamine deficiency results in pyruvate dehydrogenase dysfunction, preventing pyruvate oxidation and causing lactate accumulation. 1, 6, 3
• Severe hypothyroidism can cause hyperlactatemia. 5

Malignancy

Certain malignancies cause lactate overproduction through increased glycolytic activity in rapidly dividing tumor cells. 7, 3

Exercise and Physiologic Causes

Recent physical exertion or exercise prior to blood draw commonly causes transient lactate elevation through increased muscle glycolysis. 6 During labor, lactate levels transiently elevate, making it inappropriate for diagnosing sepsis in this specific context. 1

Critical Clinical Distinctions

"Cryptic Shock" Phenomenon

Up to 23% of septic patients have lactate ≥2 mmol/L with central venous oxygen saturation (ScvO2) >70%, representing a "cryptic shock" state that doesn't fit traditional shock definitions. 1 This occurs because severe sepsis causes low oxygen extraction ratios, making ScvO2 unreliable for directing therapy. 1 Normal or high ScvO2 values do not rule out persistent tissue hypoxia in septic patients due to impaired cellular oxygen utilization at the mitochondrial level. 1

Lactate/Pyruvate Ratio

The lactate/pyruvate ratio helps distinguish mechanisms—a ratio <18 suggests adequate tissue oxygenation with metabolic derangement, while elevated ratios indicate true tissue hypoxia. 1, 4

Common Clinical Pitfalls

• Don't ignore elevated lactate in seemingly stable patients, as it may indicate occult tissue hypoperfusion requiring intervention. 1
• Don't assume elevated lactate always means inadequate resuscitation in patients on epinephrine or other beta-agonists, as these medications directly increase lactate production. 1
• Don't rely on blood pressure alone to assess tissue perfusion in sepsis—patients can maintain normal blood pressure through compensatory mechanisms while experiencing significant tissue hypoperfusion. 1
• Don't overlook mesenteric ischemia when lactate elevation accompanies abdominal pain, even with normal imaging initially. 1, 6
• Improper sample handling causes false elevation—samples should be collected in prechilled fluoride-oxalate tubes, transported on ice, and processed within 4 hours without tourniquet or fist-clenching. 5, 6