What are the causes of lactic acidosis (elevated lactate levels)?

From the Guidelines

Lactic acidosis is primarily caused by tissue hypoxia and inadequate oxygen delivery, as well as by certain medications, toxins, and underlying diseases. The causes of lactic acidosis can be categorized into two main types: Type A and Type B. Type A lactic acidosis results from tissue hypoxia and inadequate oxygen delivery, occurring in conditions such as shock, severe anemia, carbon monoxide poisoning, and cardiac arrest, as seen in studies on trauma patients 1. In these situations, cells switch to anaerobic metabolism, producing lactic acid when oxygen is insufficient. Type B lactic acidosis occurs without tissue hypoxia and is further divided into three subtypes: B1 is associated with underlying diseases like diabetes, malignancies, and liver disease; B2 is caused by medications and toxins including metformin, alcohols, salicylates, and nucleoside reverse transcriptase inhibitors, as noted in the management of HIV-infected individuals 1; and B3 results from inborn errors of metabolism such as mitochondrial myopathies. Some conditions can cause mixed types, like sepsis, which initially causes Type A acidosis from hypoperfusion but may progress to Type B from cytokine-mediated mitochondrial dysfunction. Recognizing the specific cause is crucial for appropriate management, which typically involves treating the underlying condition, supporting circulation and oxygenation, and in severe cases, may require bicarbonate therapy or even dialysis for drug-induced cases like metformin-associated lactic acidosis, as discussed in the context of metformin use in patients with diabetes 1.

Key factors to consider in the management of lactic acidosis include:

• Identifying and addressing the underlying cause, whether it be tissue hypoxia, medication-induced, or related to an underlying disease process.
• Supporting circulation and oxygenation to reduce tissue hypoxia and promote aerobic metabolism.
• Monitoring lactate levels and adjusting treatment accordingly, as elevated lactate levels are associated with increased mortality and morbidity in critically ill patients 1.
• Considering the use of bicarbonate therapy or dialysis in severe cases, although the evidence for these interventions is not strong and should be approached with caution 1.

Overall, the management of lactic acidosis requires a comprehensive approach that takes into account the underlying cause, the severity of the condition, and the individual patient's needs and circumstances. The most recent and highest quality study on the topic, published in 2021, highlights the importance of careful metformin use in patients at risk for lactic acidosis 1.

From the FDA Drug Label

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. Drug interactions —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. 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) 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 (elevated lactate levels) include:

• Renal impairment: The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment.
• Drug interactions: Concomitant use of metformin with specific drugs that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation.
• Age 65 or greater: Elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment.
• Radiologic studies with contrast: Administration of intravascular iodinated contrast agents can lead to an acute decrease in renal function and the occurrence of lactic acidosis.
• Hypoxic states: Conditions such as acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, sepsis, and other conditions associated with hypoxemia.
• 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 2, 2.

From the Research

Causes of Lactic Acidosis

Lactic acidosis is a condition characterized by elevated lactate levels, which can occur due to various causes. The main causes of lactic acidosis can be categorized into two types: overproduction of lactate and underutilization of lactate.

• Overproduction of lactate: This type of lactic acidosis, also known as Type A, occurs when the body must regenerate ATP without oxygen (tissue hypoxia) 3. Common causes of overproduction of lactate include:
  • Circulatory, pulmonary, or hemoglobin transfer disorders
  • Cyanide poisoning
  • Certain malignancies, such as hematological conditions like multiple myeloma, leukemia, and lymphoma 4
  • Metformin use, particularly in patients with risk factors like renal dysfunction, liver disease, and heavy alcohol ingestion 5, 6
• Underutilization of lactate: This type of lactic acidosis occurs when the body is unable to remove lactate effectively. Common causes of underutilization of lactate include:
  • Liver disease, which can impair the aerobic metabolism of lactate by mitochondria in hepatocytes 3, 7
  • Inhibition of gluconeogenesis
  • Pyruvate dehydrogenase (thiamine) deficiency
  • Uncoupling of oxidative phosphorylation
  • Kidney disease, which can reduce lactate removal 3

Risk Factors

Certain risk factors can increase the likelihood of developing lactic acidosis, including:

• Renal dysfunction 5, 6
• Liver disease 5, 3, 7
• Heavy alcohol ingestion 5
• Metformin use, particularly in patients with underlying severe renal and cardiac dysfunction 3, 6
• Severe infection, dehydration, and acute kidney insufficiency 6