What are the causes of worsening lactic acidosis?

From the Guidelines

Lactic acidosis can worsen due to several key factors, including metformin use in patients with renal impairment, as evidenced by a recent study showing an increased incidence of lactic acidosis in patients with type 2 diabetes and COVID-19 taking metformin 1. The causes of worsening lactic acidosis can be multifactorial, including:

• Tissue hypoxia: Inadequate oxygen delivery to tissues is a primary cause of worsening lactic acidosis, which can result from shock, severe anemia, or respiratory failure.
• Impaired lactate clearance: Liver dysfunction reduces the body's ability to metabolize lactate, leading to accumulation.
• Increased lactate production: Certain conditions like seizures, intense exercise, or tumor lysis syndrome can rapidly increase lactate production.
• Medications: Some drugs, particularly metformin in patients with renal impairment, can contribute to lactic acidosis, as metformin should be avoided in patients at risk for lactic acidosis, such as those with anaerobic metabolism, impaired metformin clearance, or impaired lactic acid clearance 1.
• Underlying diseases: Sepsis, diabetic ketoacidosis, and certain inherited metabolic disorders can exacerbate lactic acidosis. To address worsening lactic acidosis, focus on treating the underlying cause, improving tissue oxygenation, and supporting organ function, and consider discontinuing metformin in patients at risk for lactic acidosis or with increased lactate concentrations 1. In severe cases, consider bicarbonate therapy or renal replacement therapy to help clear lactate and correct acidosis, and monitor lactate levels, acid-base status, and tissue perfusion closely to guide management.

From the FDA Drug Label

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. Metformin associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. 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 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. 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) Excessive alcohol intake —Alcohol potentiates the effect of metformin on lactate metabolism

The causes of worsening lactic acidosis include:

• Renal impairment: Significant renal impairment increases the risk of metformin accumulation and lactic acidosis.
• Drug interactions: Concomitant use of certain 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, increasing the risk of lactic acidosis.
• 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.
• 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: 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, increasing the risk of lactic acidosis 2.

From the Research

Causes of Worsening Lactic Acidosis

• Metformin use is a common cause of lactic acidosis, particularly in patients with risk factors such as renal impairment, liver disease, and excessive alcohol consumption 3, 4, 5, 6, 7
• Renal impairment can lead to metformin accumulation, increasing the risk of lactic acidosis 3, 4, 6, 7
• Liver disease can also contribute to the development of lactic acidosis, as the liver plays a key role in lactate clearance 3
• Other risk factors for lactic acidosis include malignancy, use of certain medications, and underlying vascular disease 4, 5
• Acute kidney injury (AKI) can also trigger lactic acidosis in patients taking metformin 5

Pathophysiology of Lactic Acidosis

• Metformin inhibits mitochondrial oxidative phosphorylation, leading to reduced lactate clearance and increased lactate production 4
• The liver is a key organ in the development of lactic acidosis, as it is responsible for lactate clearance and metformin metabolism 3
• Mitochondrial impairment and adenosine triphosphate depletion can contribute to the development of lactic acidosis 3

Clinical Presentation and Diagnosis

• Symptoms of lactic acidosis can be non-specific, including gastrointestinal symptoms, abdominal pain, and nausea 5
• Diagnosis is typically made based on the presence of high anion gap metabolic acidosis and elevated lactate levels 4
• Risk factors such as metformin use, renal impairment, and liver disease should be considered when diagnosing lactic acidosis 3, 4, 5, 6, 7