What causes lactic acidosis?

From the Guidelines

Lactic acidosis is primarily caused by tissue hypoxia and metabolic dysfunction, with metformin being a significant contributor to the risk of developing this condition, especially in patients with impaired renal function or those at risk for anaerobic metabolism 1.

Causes of Lactic Acidosis

The primary causes of lactic acidosis can be categorized into two types:

• Type A, which occurs due to tissue hypoxia, forcing cells to switch to anaerobic metabolism and produce lactic acid. Common causes include:
  • Shock
  • Severe hypotension
  • Cardiac arrest
  • Severe anemia
  • Carbon monoxide poisoning
  • Severe hypoxemia
• Type B, which occurs without tissue hypoxia and can result from:
  • Medications such as metformin and nucleoside reverse transcriptase inhibitors
  • Liver dysfunction
  • Malignancies
  • Seizures
  • Thiamine deficiency
  • Certain inborn errors of metabolism Other causes include excessive exercise, diabetic ketoacidosis, and alcohol intoxication.

Mechanism and Risk Factors

The underlying mechanism involves impaired clearance of lactate by the liver or increased production of lactate that exceeds the body's ability to metabolize it, leading to metabolic acidosis characterized by decreased pH, low bicarbonate levels, and an increased anion gap. Metformin, in particular, increases the risk of lactic acidosis, especially in patients with significant renal impairment, as it can accumulate to toxic levels 1. The risk is also higher in patients with conditions that impair lactic acid clearance, such as liver failure.

Clinical Considerations

In patients at risk for lactic acidosis, metformin should be avoided or used with caution, and lactate concentrations should be monitored closely 1. The decision to use metformin should be based on the patient's individual risk factors, including renal function, and the potential benefits of metformin therapy should be weighed against the risk of lactic acidosis. In cases where metformin is used, it is essential to follow guidelines for dose adjustment based on renal function and to monitor patients closely for signs 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. Lactic acidosis is a medical emergency and must be treated in a hospital. You have a higher chance of getting lactic acidosis if you: have kidney problems. People whose kidneys are not working properly should not take metformin hydrochloride tablets. 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). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough 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.

Causes of Lactic Acidosis:

• Kidney problems
• Liver problems
• Congestive heart failure
• Excessive alcohol consumption
• Dehydration
• Certain x-ray tests with injectable dyes or contrast agents
• Surgery
• Heart attack
• Severe infection
• Stroke
• Age 80 or older with unknown kidney function 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 the accumulation of metformin in patients with renal impairment 3, 4, 5, 6
• Renal impairment, either pre-existing or acute, can lead to the accumulation of metformin, increasing the risk of lactic acidosis 3, 4, 5, 6
• Other factors that can contribute to the development of lactic acidosis include:
  • Intercurrent deterioration of diabetic nephropathy 5
  • Gastrointestinal fluid loss accompanied by the continued use of an angiotensin-converting enzyme inhibitor 4
  • Sepsis, fever, diarrhea, vomiting, which can reduce metformin renal clearance 7
• Metformin has a large volume of distribution and accumulates in erythrocytes and intestinal cells, resulting in less efficient removal with dialysis and rebound lactic acidosis 4

Risk Factors

• Patients with type 2 diabetes who are taking metformin are at risk of developing lactic acidosis, particularly if they have renal impairment or other predisposing factors 3, 4, 5, 6, 7
• The risk of lactic acidosis is increased in patients who continue to take metformin despite having a concomitant disease or situation that reduces metformin renal clearance 7
• Patients with chronic nephropathy may be at higher risk of developing lactic acidosis due to metformin accumulation 5, 7