What are the causes of lactic acidosis?

From the Guidelines

Lactic acidosis is primarily caused by an imbalance between lactic acid production and clearance in the body, often resulting from tissue hypoxia, certain medications, and medical conditions that impair lactate clearance. This occurs when tissues receive inadequate oxygen, forcing cells to switch from aerobic to anaerobic metabolism, which produces lactic acid as a byproduct.

Common Causes of Lactic Acidosis

• Shock (cardiogenic, septic, or hypovolemic)
• Severe infections
• Cardiac arrest
• Severe trauma
• Intense exercise Certain medications can also trigger lactic acidosis, particularly metformin (especially in patients with kidney dysfunction) 1, nucleoside reverse transcriptase inhibitors used in HIV treatment, and propofol when administered in high doses for prolonged periods. Medical conditions that impair lactate clearance, such as liver disease or kidney failure, can exacerbate the condition. Additionally, some inherited metabolic disorders affecting mitochondrial function can lead to chronic lactic acidosis. The severity of lactic acidosis correlates with blood lactate levels, with values above 4 mmol/L generally indicating significant tissue hypoperfusion.

Key Factors to Consider

• Tissue hypoxia due to various causes, including hypoxemia, low cardiac output states, or sepsis 1
• Medication-induced lactic acidosis, particularly with metformin in patients with renal impairment 1
• Underlying medical conditions that impair lactate clearance, such as liver or kidney disease Treatment focuses on addressing the underlying cause while supporting vital functions, as lactic acidosis itself is a marker of serious illness rather than a primary disease. It is essential to identify and manage the underlying cause of lactic acidosis to improve patient outcomes and reduce morbidity and mortality. In patients at risk for lactic acidosis, such as those with anaerobic metabolism (e.g., sepsis, hypoxia), impaired metformin clearance (significant renal impairment), or impaired lactic acid clearance (liver failure), metformin should be avoided or used with caution 1. Regular monitoring of lactate levels and kidney function is crucial in patients receiving metformin, especially in those with underlying medical conditions that may increase the risk of lactic acidosis.

From the FDA Drug Label

Metformin hydrochloride, the medicine in metformin hydrochloride tablets, can cause a rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. You have a higher chance of getting lactic acidosis if you:

• have kidney problems.
• have liver problems.
• have congestive heart failure that requires treatment with medicines
• drink a lot of alcohol (very often or short-term "binge" drinking).
• get dehydrated (lose a large amount of body fluids).
• have certain x-ray tests with injectable dyes or contrast agents.
• have surgery
• have a heart attack, severe infection, or stroke.
• are 80 years of age or older and have not had your kidney function tested.

The causes of lactic acidosis include:

• Kidney problems: Metformin accumulation due to reduced renal excretion increases the risk of lactic acidosis.
• Liver problems: Impaired lactate clearance can lead to higher lactate blood levels.
• Congestive heart failure: Requires treatment with medicines and can increase the risk of lactic acidosis.
• Excessive alcohol intake: Potentiates the effect of metformin on lactate metabolism.
• Dehydration: Loss of body fluids can increase the risk of lactic acidosis.
• Radiologic studies with contrast: Administration of intravascular iodinated contrast agents can lead to acute decrease in renal function and lactic acidosis.
• Surgery and other procedures: Withholding of food and fluids can increase the risk of volume depletion, hypotension, and renal impairment.
• Hypoxic states: Conditions such as acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, sepsis, and other conditions associated with hypoxemia can increase the risk of lactic acidosis.
• Age 80 or older: Increased risk due to potential decline in renal function. 2, 2, 2

From the Research

Causes of Lactic Acidosis

• Metformin-associated lactic acidosis (MALA) is a severe metabolic failure with high related mortality, often caused by decreased elimination of metformin due to renal dysfunction 3, 4, 5
• Lactic acidosis can also be caused by increased production of L-lactic acid, which can occur in situations such as sepsis, fever, diarrhea, and vomiting 6, 5
• Acute overdose of metformin can also lead to lactic acidosis, even in patients without renal dysfunction 7
• Other factors that can contribute to the development of lactic acidosis include:
  • Acute tubular necrosis from gastrointestinal fluid loss 3
  • Continued use of angiotensin-converting enzyme inhibitors in patients with type 2 diabetes 3
  • Reduced metformin renal clearance due to concomitant diseases or situations such as sepsis, fever, diarrhea, and vomiting 5

Pathophysiology of Lactic Acidosis

• Lactic acidosis is characterized by an imbalance in the body's acid-base balance, with increased production or decreased removal of L-lactic acid 6
• Metformin accumulates in erythrocytes and intestinal cells, resulting in less efficient removal with dialysis and rebound lactic acidosis 3
• Continuous renal replacement therapy (CRRT) can efficiently treat metformin-associated lactic acidosis by eliminating metformin and correcting acidosis, electrolyte alterations, and maintaining fluid balance 4, 5