What causes lactic acidosis, especially in patients with diabetes, renal impairment, or those taking metformin?

Causes of Lactic Acidosis

Lactic acidosis develops primarily from tissue hypoxia (Type A) or metabolic disturbances without hypoxia (Type B), with metformin accumulation in renal impairment being the most critical drug-related cause that clinicians must recognize and prevent. 1

Type A Lactic Acidosis: Tissue Hypoxia and Hypoperfusion

Type A lactic acidosis results from inadequate oxygen delivery to tissues, triggering anaerobic metabolism and lactate accumulation. 1

Primary Causes:

• Circulatory shock (septic, cardiogenic, hypovolemic) causing inadequate tissue perfusion 1
• Severe infections, particularly in patients with diabetes mellitus 1
• Cardiac failure with reduced cardiac output 1
• Acute mesenteric ischemia - particularly suspect when lactate >2 mmol/L occurs with elevated urea and abdominal pain (88% of patients with acute mesenteric ischemia present with metabolic acidosis) 1

Critical Pitfall:

Do not ignore the combination of lactic acidosis with elevated urea and abdominal pain, even when the patient appears clinically stable - this strongly suggests mesenteric ischemia requiring immediate CT angiography, as diagnostic delay is the dominant factor in mortality (30-70%). 1

Type B Lactic Acidosis: Metabolic and Drug-Induced

Type B lactic acidosis occurs without tissue hypoxia, primarily from impaired lactate clearance or mitochondrial dysfunction. 1

Metformin-Associated Lactic Acidosis (MALA)

Metformin is the most clinically significant drug cause of lactic acidosis, with incidence of 2-9 per 100,000 patients/year, but risk increases dramatically with renal impairment. 1

High-Risk Conditions for MALA:

• Renal impairment with eGFR <30 mL/min/1.73 m² (metformin is contraindicated) 2, 3
• eGFR 30-45 mL/min/1.73 m² (dose reduction to 1000 mg daily required) 3
• Acute kidney injury from any cause (sepsis, dehydration, NSAIDs, ACE inhibitors) 3, 4
• Sepsis or systemic infection with hemodynamic instability 1
• Hypoxic states (respiratory failure, severe COPD exacerbation) 1
• Liver disease (impairs lactate clearance since liver is the major site of lactate removal) 1
• Acute heart failure 2
• COVID-19 infection (adjusted hazard ratio 4.46 for lactic acidosis in metformin users, associated with higher doses, worse kidney function, and greater COVID-19 severity) 3

Mechanism:

Metformin decreases hepatic lactate uptake and is substantially excreted by the kidney; renal impairment causes drug accumulation, leading to impaired lactate clearance and increased lactate production. 2 Metformin has a large volume of distribution and accumulates in erythrocytes and intestinal cells. 4

Clinical Presentation:

Subtle, nonspecific symptoms precede severe acidosis: malaise, myalgias, abdominal pain, respiratory distress, increased somnolence, nausea, vomiting, generalized weakness. 2, 1 Do not ignore these symptoms in metformin users. 1

When to Stop Metformin Immediately:

• 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
• Any acute illness causing dehydration, vomiting, diarrhea, fever 5
• Sepsis or shock 3
• Acute kidney injury 3
• Hypoxia 3
• Before surgery requiring NPO status 1

Other Medication Causes:

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) - particularly stavudine and didanosine - cause mitochondrial toxicity leading to lactic acidosis, with incidence of 1.3 cases per 1,000 person-years of NRTI exposure. 1 Risk factors include obesity, female sex, prolonged use (>6 months), and pregnancy. 1

Metabolic and Organ Dysfunction:

• Renal impairment reduces lactate clearance (30-65% of adults with chronic kidney disease have hyperlactatemia) 1
• Liver disease impairs lactate clearance through gluconeogenesis and oxidation 1
• Severe hypothyroidism 1
• Thiamine deficiency (impairs pyruvate dehydrogenase function) 1

Rhabdomyolysis-Induced Lactic Acidosis:

Damaged muscle tissue undergoes anaerobic metabolism during rhabdomyolysis, producing lactate. 1 This is particularly dangerous in sickle cell trait patients with exertional rhabdomyolysis, who can develop the lethal triad of lactic acidosis, hyperkalemia, and cardiac dysfunction. 1

D-Lactic Acidosis:

Occurs in patients with short bowel syndrome and preserved colon, where bacterial overgrowth produces D-lactate from carbohydrate fermentation. 1 Standard lactate assays measure only L-lactate, so D-lactic acidosis may be missed. 1

Diagnostic Criteria

Laboratory findings defining lactic acidosis: 1

• Arterial pH <7.3 (some sources use <7.35)
• Lactate >2 mmol/L (elevated), >5 mmol/L (abnormal), >10 mmol/L (serious/life-threatening)
• Increased anion gap (Na - [Cl + CO₂] >16)
• Metformin level >5 mcg/mL in MALA (though not widely available) 2

Proper Lactate Measurement Technique:

Use prechilled fluoride-oxalate tubes, transport on ice, process within 4 hours, collect without tourniquet or fist-clenching. 1 Single measurements can be falsely elevated by these technical errors.

Prevention Strategy

The most critical intervention is prevention through patient education and appropriate prescribing. 5

• Monitor eGFR at least annually in all metformin users; increase to every 3-6 months when eGFR <60 mL/min/1.73 m² 3
• Educate patients to stop metformin and seek medical care during any acute illness causing dehydration, vomiting, or reduced oral intake 4, 5
• Use eGFR, not creatinine alone, for renal function assessment (creatinine varies by age, ethnicity, muscle mass) 1
• Avoid metformin in patients with anaerobic metabolism (sepsis, hypoxia), impaired metformin clearance (significant renal impairment), or impaired lactate clearance (liver failure) 3