What causes lactic acidosis?

From the Guidelines

Lactic acidosis is primarily caused by an accumulation of lactic acid in the bloodstream due to inadequate oxygen delivery to tissues, certain medications like metformin, especially in patients with renal impairment, and other factors such as intense exercise, seizures, liver disease, and inherited metabolic disorders. The condition occurs when there is inadequate oxygen delivery to tissues or when the body cannot properly utilize oxygen, forcing cells to switch to anaerobic metabolism. Common causes include shock (cardiogenic, septic, or hypovolemic), severe hypoxemia, carbon monoxide poisoning, severe anemia, and certain medications like metformin, especially in patients with renal impairment 1. Other causes include:

• Intense exercise
• Seizures
• Liver disease
• Certain malignancies
• Inherited metabolic disorders Type A lactic acidosis results from tissue hypoxia and inadequate perfusion, while Type B occurs despite normal tissue oxygenation, often due to medications, toxins, or metabolic disorders 1. The body normally clears lactate through the liver and kidneys, so dysfunction in these organs can also contribute to lactic acid buildup 1. Symptoms include rapid breathing, confusion, fatigue, nausea, and in severe cases, cardiovascular collapse. It is essential to identify and manage the underlying cause of lactic acidosis to prevent morbidity and mortality, and metformin should be used with caution in patients with risk factors for lactic acidosis, such as renal impairment, and discontinued if necessary 1.

From the FDA Drug Label

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal impairment — The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment The concomitant use of metformin hydrochloride tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation Age 65 or greater —The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. 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. Surgery and other procedures —Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. 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) Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. Excessive alcohol intake —Alcohol potentiates the effect of metformin on lactate metabolism Hepatic impairment —Patients with hepatic impairment have developed cases of metformin- associated lactic acidosis.

The causes of lactic acidosis include:

• Renal impairment
• Drug interactions that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation
• Age 65 or greater due to a greater likelihood of having hepatic, renal, or cardiac impairment
• Radiologic studies with contrast that lead to an acute decrease in renal function
• Surgery and other procedures that may increase the risk for volume depletion, hypotension, and renal impairment
• Hypoxic states such as acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, sepsis, and other conditions associated with hypoxemia
• Excessive alcohol intake that potentiates the effect of metformin on lactate metabolism
• Hepatic impairment that may lead to impaired lactate clearance and higher lactate blood levels 2

From the Research

Causes of Lactic Acidosis

• Lactic acidosis can be caused by metformin use, particularly in patients with risk factors such as kidney and liver conditions, malignancy, or use of certain medications 3, 4, 5
• Metformin-associated lactic acidosis (MALA) can occur when patients continue to take the drug in the face of a concomitant disease or situation such as sepsis, fever, diarrhea, vomiting, which reduces metformin renal clearance 4
• Acute kidney injury (AKI) can also contribute to the development of lactic acidosis in patients taking metformin 3, 5
• Other factors that can increase the risk of lactic acidosis include poor oral intake, excessive antibiotic use, and use of renin-angiotensin system blockade 3, 5

Risk Factors for Lactic Acidosis

• Diabetes, particularly type 2 diabetes mellitus (DM) 3, 4, 5, 6
• Kidney disease or renal dysfunction 3, 4, 5
• Liver disease or liver dysfunction 4, 5
• Malignancy 4, 5
• Use of certain medications, such as angiotensin-converting enzyme inhibitors 3

Prevention and Treatment

• Patients taking metformin should be counseled to stop the drug and seek medical care in the setting of illnesses or situations that may reduce metformin renal clearance 3, 4
• Treatment of lactic acidosis may involve hemodialysis, continuous renal replacement therapy (CRRT), or bicarbonate infusion 3, 4, 7, 6
• Aggressive treatment strategies, such as hemodialysis followed by peritoneal dialysis, continuous bicarbonate infusion, and tight glucose control, may be necessary to improve outcomes 6