What conditions predispose to lactic acidosis?

Conditions Predisposing to Lactic Acidosis

Lactic acidosis develops when tissue hypoxia, impaired lactate clearance, or mitochondrial dysfunction disrupts normal lactate metabolism, with the most critical predisposing conditions being renal impairment, sepsis/shock, liver disease, and certain medications—particularly metformin in the setting of acute illness. 1, 2

Type A Lactic Acidosis: Tissue Hypoxia and Hypoperfusion

Type A lactic acidosis results from inadequate tissue oxygenation and represents the most common and immediately life-threatening category. 3

Circulatory Disorders

• Shock states of any etiology (cardiogenic, septic, hypovolemic, distributive) cause inadequate tissue perfusion and force cells into anaerobic metabolism 3
• Acute myocardial infarction with cardiovascular collapse creates regional and systemic hypoperfusion 2
• Acute congestive heart failure, particularly when accompanied by hypoperfusion and hypoxemia, is a well-documented precipitant 2
• Cardiac arrest and resuscitation states generate massive lactate production 3

Severe Infections

• Sepsis and septic shock are among the most common causes, with 88% of patients with acute mesenteric ischemia presenting with metabolic acidosis and elevated lactate 3
• Lactate ≥2 mmol/L defines sepsis-induced tissue hypoperfusion even without hypotension 3
• Severe infections in patients with underlying diabetes mellitus carry particularly high risk 3

Tissue Ischemia

• Acute mesenteric ischemia presents with the triad of abdominal pain, elevated lactate, and elevated urea; lactate >2 mmol/L predicts irreversible intestinal ischemia (HR 4.1,95% CI 1.4-11.5) 3
• Limb ischemia from arterial occlusion or compartment syndrome 3

Respiratory Failure

• Severe hypoxemia from any cause (ARDS, pneumonia, pulmonary embolism) impairs oxygen delivery 2
• Chronic pulmonary disease with acute decompensation 1

Type B Lactic Acidosis: Metabolic and Drug-Induced

Type B lactic acidosis occurs without tissue hypoxia, typically from impaired lactate clearance or mitochondrial dysfunction. 3

Renal Impairment (Critical Risk Factor)

Renal dysfunction is the single most important predisposing factor for metformin-associated lactic acidosis because the kidney is responsible for both metformin elimination and lactate clearance. 2, 4

• eGFR <30 mL/min/1.73 m² represents absolute contraindication to metformin use 2
• eGFR 30-45 mL/min/1.73 m² requires dose reduction and careful monitoring; initiation not recommended 1, 2
• Acute kidney injury from any cause (volume depletion, nephrotoxins, contrast agents) dramatically increases risk 2, 5
• Renal impairment reduces lactate clearance independent of medication use, with hyperlactatemia reported in 30-65% of adults with chronic kidney disease 3

Hepatic Impairment

Liver disease impairs lactate clearance since the liver is the major site of lactate removal through gluconeogenesis and oxidation. 3

• Cirrhosis of any etiology reduces hepatic lactate metabolism 4
• Acute liver failure or severe hepatic dysfunction 1, 2
• Patients with clinical or laboratory evidence of hepatic disease should avoid metformin 2

Medication-Induced Lactic Acidosis

Metformin (Most Clinically Significant)

• Incidence: 2-9 cases per 100,000 patient-years in general population, but risk increases dramatically with renal impairment 3, 4
• In COVID-19 patients with type 2 diabetes, metformin use increased lactic acidosis risk (adjusted HR 4.46,95% CI 1.11-18.0) 1
• Risk factors include: higher doses, worse kidney function, acute illness severity, elderly age (≥65 years), and concurrent conditions 1, 3, 2

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• Stavudine and didanosine carry highest risk through mitochondrial DNA polymerase γ inhibition 3
• Incidence: 1.3 cases per 1,000 person-years of NRTI exposure 3
• Risk factors: obesity, female sex, prolonged use (>6 months), pregnancy 3
• Newer antiretrovirals have largely replaced these agents, reducing incidence 3

Conditions Affecting Lactate Metabolism

Alcohol

• Excessive alcohol intake potentiates metformin's effect on lactate metabolism 2
• Alcohol impairs hepatic gluconeogenesis and lactate clearance 2

Malignancy

• Advanced malignancies, particularly hematologic, can cause Type B lactic acidosis through increased glycolysis 3

Rhabdomyolysis

• Damaged muscle tissue undergoes anaerobic metabolism, producing lactate 3
• Particularly dangerous in sickle cell trait patients with exertional rhabdomyolysis 3
• Associated complications include hyperkalemia and hypocalcemia, potentially leading to cardiac arrest 3

Metabolic Disorders

• Inborn errors of metabolism including methylmalonic acidemia, propionic acidemia, and maple syrup urine disease 3
• Thiamine deficiency impairs pyruvate dehydrogenase function 3
• D-lactic acidosis in patients with short bowel syndrome and preserved colon 3

Endocrine Disorders

• Severe primary hypothyroidism can cause hyperlactatemia 3
• Deficiency of tetrahydrobiopterin affects up to 80% of patients 3

High-Risk Clinical Scenarios Requiring Immediate Metformin Discontinuation

Metformin must be stopped immediately in the following situations to prevent lactic acidosis: 2

• Sepsis or systemic infection with hemodynamic instability 1, 2
• Acute kidney injury or anticipated renal impairment 2, 5
• Hypoxic states: acute CHF, respiratory failure, shock 2
• Before iodinated contrast procedures in patients with eGFR 30-60 mL/min/1.73 m², history of liver disease, alcoholism, heart failure, or receiving intra-arterial contrast 2
• Surgical procedures requiring NPO status and potential volume depletion 2
• Acute myocardial infarction or cardiovascular collapse 2

Age-Related Risk

• Age ≥65 years increases risk due to higher likelihood of hepatic, renal, or cardiac impairment 2
• Elderly patients in biguanide-associated lactic acidosis studies had higher mortality (50.3% overall) 6
• More frequent renal function assessment required in elderly patients on metformin 2

Critical Pitfalls to Avoid

Do not ignore hyperlactatemia (≥2 mmol/L) even in the absence of hypotension, as it may indicate occult tissue hypoperfusion or organ dysfunction requiring urgent evaluation. 3

Do not continue metformin in hospitalized patients with acute illness, particularly those with COVID-19, sepsis, or any condition causing hypoxia or hemodynamic instability. 1

Do not delay imaging in suspected mesenteric ischemia—the combination of abdominal pain, elevated lactate, and elevated urea demands immediate CT angiography, as diagnostic delay is the dominant factor in mortality (30-70%). 3

Do not assume metformin is safe simply because creatinine appears normal—use eGFR for accurate assessment, as creatinine varies widely based on age, ethnicity, and muscle mass. 1