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 medications or underlying conditions such as metformin, especially with kidney dysfunction, as seen in a study published in The Lancet Diabetes and Endocrinology in 2021 1. The causes of lactic acidosis can be categorized into two main types:

• Type A, which is caused by tissue hypoxia due to inadequate oxygen delivery, leading to anaerobic metabolism, as seen in shock, severe heart failure, respiratory failure, and severe anemia.
• Type B, which is caused by medications or underlying conditions without hypoxia, including metformin (especially with kidney dysfunction), nucleoside reverse transcriptase inhibitors, alcoholism, liver disease, malignancies, and certain inborn errors of metabolism. Other important causes of lactic acidosis include:
• Excessive exercise, which can temporarily increase lactate levels due to increased muscle metabolism.
• Seizures and severe infections, particularly sepsis, which can lead to lactic acidosis due to increased metabolic demand and impaired oxygen delivery. The pathophysiology of lactic acidosis involves cells switching to anaerobic glycolysis when oxygen is insufficient, producing lactate from pyruvate, which generates less ATP than aerobic metabolism and creates hydrogen ions that lower blood pH. Treatment of lactic acidosis focuses on addressing the underlying cause while supporting vital functions, and in severe cases, may include sodium bicarbonate administration to temporarily buffer excess acid, although its use is not recommended in patients with hypoperfusion-induced lactic acidemia with pH ≥ 7.15, as stated in the Surviving Sepsis Campaign guidelines published in Critical Care Medicine in 2017 1.

From the FDA Drug Label

The onset of metformin associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

The causes of lactic acidosis include:

• Renal impairment: 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 2.
• Concomitant use of certain drugs: Such as carbonic anhydrase inhibitors like topiramate 2.
• Age 65 years old 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 2.
• Radiological 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 2.
• 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 2.
• Hypoxic states: Such as acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, sepsis, and other conditions associated with hypoxemia 2.
• Excessive alcohol intake: Alcohol potentiates the effect of metformin on lactate metabolism 2.
• Hepatic impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis, possibly due to impaired lactate clearance resulting in higher lactate blood levels 2.

From the Research

Causes of Lactic Acidosis

The causes of lactic acidosis can be attributed to various factors, including:

• Metformin-associated lactic acidosis (MALA), which is a rare but serious complication of metformin use, associated with high mortality 3, 4, 5, 6
• Disruption in renal function, resulting in the accumulation of metformin 3
• Acute renal failure, which can be caused by dehydration, excessive drinking, or the use of certain medications such as angiotensin-converting-enzyme (ACE) inhibitors 3, 4
• Sepsis or low-flow states, which can lead to tissue hypoxia and epinephrine-induced stimulation of aerobic glycolysis 7
• Pyelonephritis-induced septic shock, which can incite metformin-associated lactic acidosis 5
• Gastrointestinal fluid loss, accompanied by the continued use of an angiotensin-converting enzyme inhibitor 4
• Intermittent nausea and vomiting, which can lead to dehydration and electrolyte imbalances 4

Risk Factors

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

• Renal insufficiency or hypoperfusion 5
• Use of metformin, especially in patients with type 2 diabetes 3, 4, 5, 6
• Use of renin-angiotensin system blockade, which can increase the risk of kidney dysfunction 4
• Dehydration and excessive drinking 3, 4
• Sepsis or low-flow states 7

Clinical Presentation

Lactic acidosis can present with various symptoms, including:

• Nausea, vomiting, and fatigue, which can mimic sepsis 3
• Respiratory distress, hypotension, and hypoglycemia 3
• Severe metabolic acidosis with a high anion gap and blood lactate level 6
• Profound hypotension and acute respiratory failure 6