What causes lactic acidosis?

Causes of Lactic Acidosis

Lactic acidosis is primarily caused by tissue hypoxia resulting from decreased oxygen delivery, low cardiac output states, or conditions like sepsis where oxygen consumption is impaired despite adequate oxygen delivery. 1

Classification and Pathophysiology

Lactic acidosis can be broadly classified based on the predominant mechanism:

1. Increased Production (Type A)

• Tissue hypoxia conditions:
  • Circulatory failure (shock, cardiac arrest)
  • Respiratory failure
  • Severe anemia
  • Carbon monoxide poisoning
• Sepsis - causes impaired oxygen utilization despite adequate delivery
• Exercise - intense physical activity can cause transient lactic acidosis
• Seizures - increased muscle activity and oxygen demand

2. Decreased Clearance (Type B)

• Liver disease - impaired lactate metabolism
• Renal impairment - reduced lactate excretion
• Medications:
  • Metformin - inhibits mitochondrial respiration in the liver 2
  • Nucleoside reverse transcriptase inhibitors (NRTIs) - inhibit mitochondrial DNA polymerase γ 1
• Thiamine deficiency - impairs pyruvate dehydrogenase function
• Inherited metabolic disorders - affecting lactate metabolism

Medication-Induced Lactic Acidosis

Metformin

Metformin can cause lactic acidosis through inhibition of mitochondrial respiration, particularly in the liver. However, metformin-associated lactic acidosis (MALA) typically requires both:

1. Elevated plasma metformin concentrations (as in renal impairment)
2. A secondary event disrupting lactate metabolism (e.g., cirrhosis, sepsis, hypoperfusion) 2, 3

Risk factors for MALA include:

• eGFR <45 mL/min/1.73m²
• Hepatic impairment
• Excessive alcohol intake
• Hypoxic states (heart failure, respiratory failure)
• Age ≥65 years
• Radiologic studies with contrast agents 2

NRTIs

Risk factors for NRTI-induced lactic acidosis include:

• Obesity
• Female gender
• Pregnancy
• Prolonged NRTI use (particularly stavudine and didanosine) 1

Pathophysiological Mechanisms

Lactic acid accumulates when:

1. Production exceeds clearance - During anaerobic metabolism, pyruvate is converted to lactate to regenerate NAD+ when oxygen is unavailable
2. Clearance is impaired - The liver normally clears approximately 70% of produced lactate through gluconeogenesis or oxidation

When lactate production overwhelms clearance mechanisms, blood pH falls below 7.35 with elevated blood lactate levels (>5 mmol/L), resulting in lactic acidosis 1, 4.

Clinical Presentation

Early symptoms of lactic acidosis may be nonspecific:

• Nausea and vomiting
• Abdominal pain
• Dyspnea
• Generalized weakness
• Altered mental status

Laboratory findings include:

• Arterial pH <7.35
• Elevated serum lactate (>2 mmol/L)
• Increased anion gap
• Elevated liver enzymes (may be present) 1

Special Considerations

• Mesenteric ischemia should be considered in patients with lactic acidosis and abdominal pain, especially when they may not otherwise appear critically ill 1
• HIV patients on NRTIs who develop unexplained symptoms (nausea, vomiting, abdominal pain) should be evaluated for lactic acidosis 1
• Respiratory exchange ratio (RER) >1.0 during exercise testing can indicate lactic acidosis 5

Understanding the specific cause of lactic acidosis is crucial for appropriate management, as the most effective treatment is addressing the underlying condition 4, 6.