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, with the main causes including tissue hypoxia and conditions without hypoxia where metabolism is altered, as supported by the most recent study 1 from 2023. The causes of lactic acidosis can be categorized into two main types: type A, which is caused by tissue hypoxia, and type B, which occurs without hypoxia.

• Type A causes include:
  • Shock (septic, cardiogenic, or hypovolemic)
  • Severe hypoxemia
  • Carbon monoxide poisoning
  • Severe anemia
• Type B causes include:
  • Medications (metformin, nucleoside reverse transcriptase inhibitors, propofol, and linezolid)
  • Liver dysfunction
  • Kidney failure
  • Malignancies
  • Seizures
  • Certain inherited metabolic disorders
  • Excessive exercise, which can cause temporary lactic acidosis, as noted in a study from 2008 1
  • Diabetic ketoacidosis, which may present with lactic acidosis due to tissue hypoperfusion, as discussed in a study from 2021 1 Treatment of lactic acidosis focuses on addressing the underlying cause, such as improving tissue oxygenation, discontinuing offending medications, or treating infections, with sodium bicarbonate therapy generally reserved for cases with pH below 7.1, as recommended in a guideline from 2017 1. In severe cases, intravenous fluids, vasopressors, or mechanical ventilation may be required to manage lactic acidosis, as supported by a study from 2013 1. Early recognition and treatment are essential to prevent complications like organ dysfunction and cardiovascular collapse, highlighting the importance of prompt intervention in cases of lactic acidosis, as emphasized in a study from 2009 1.

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 is substantially excreted by the kidney, and the risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment.
• Liver problems: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis, possibly due to impaired lactate clearance resulting in 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: Can happen if you are sick with a fever, vomiting, or diarrhea, or if you sweat a lot with activity or exercise and do not drink enough fluids.
• Certain x-ray tests with injectable dyes or contrast agents: Can lead to an acute decrease in renal function and the occurrence of lactic acidosis.
• Surgery: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment.
• Hypoxic states: Such as acute congestive heart failure, cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia.
• Age 65 or greater: The risk of metformin-associated lactic acidosis increases with the patient's age.
• Radiologic studies with contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis.
• Hypoxic states: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). 2 2 2

From the Research

Causes of Lactic Acidosis

Lactic acidosis is a complex condition with multiple causes. The following are some of the key factors that contribute to its development:

• Hypoxia, which can be caused by septic, cardiogenic, hypovolemic, or obstructive shock 3
• Specific pathologies, such as liver disease 3, 4
• Use of certain drugs, including metformin 3, 5, 4, 6, 7
• Presence of toxins 3
• Trauma 3
• Cyanide poisoning or certain malignancies, which can lead to overproduction of lactic acid 4
• Liver disease, inhibition of gluconeogenesis, pyruvate dehydrogenase (thiamine) deficiency, and uncoupling of oxidative phosphorylation, which can impair the removal of lactic acid 4

Drug-Induced Lactic Acidosis

Metformin is a commonly used drug that can cause lactic acidosis, particularly in patients with underlying renal and cardiac dysfunction 5, 4, 6, 7. The risk of metformin-associated lactic acidosis (MALA) is increased in patients who take large doses of the drug or have impaired renal function 5, 6.

Other Factors

Other factors that can contribute to the development of lactic acidosis include:

• Acute tubular necrosis from gastrointestinal fluid loss accompanied by the continued use of an angiotensin-converting enzyme inhibitor 5
• Severe metabolic acidosis with a high anion gap and blood lactate level 6
• Profound hypotension and acute respiratory failure 6