What are the sources of lactic acidosis?

From the Guidelines

Lactic acidosis primarily stems from tissue hypoxia, where inadequate oxygen delivery forces cells to shift from aerobic to anaerobic metabolism, producing excess lactic acid, with common sources including shock states, severe hypoxemia, and medications such as metformin, especially with renal dysfunction, as noted in a recent study 1.

Common Sources of Lactic Acidosis

• Shock states (septic, cardiogenic, hypovolemic)
• Severe hypoxemia
• Carbon monoxide poisoning
• Severe anemia
• Medications:
  • Metformin, particularly with renal dysfunction 1
  • Nucleoside reverse transcriptase inhibitors
  • Propofol with prolonged infusion
  • Alcohols like ethanol and methanol

Other Causes

• Inherited metabolic disorders affecting lactate metabolism, such as pyruvate dehydrogenase deficiency and mitochondrial myopathies
• Malignancies producing lactic acid through the Warburg effect
• Seizures and extreme exercise temporarily increasing lactate levels

Treatment Approach

Treatment focuses on addressing the underlying cause while supporting circulation and oxygenation. In medication-induced cases, discontinuing the offending agent is crucial, as seen with metformin in patients at risk for lactic acidosis 1. Understanding these sources helps clinicians identify and address the root cause of lactic acidosis rather than simply treating the acidemia. Additionally, guidelines suggest against the use of sodium bicarbonate therapy to improve hemodynamics or reduce vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH ≥ 7.15 1.

From the FDA Drug Label

5 WARNINGS AND PRECAUTIONS

1. 1 Lactic Acidosis 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 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.

The sources of lactic acidosis associated with metformin use 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 2

From the Research

Lactic Acidosis Sources

• Lactic acidosis can be caused by various factors, including metformin use in patients with type 2 diabetes mellitus 3, 4, 5, 6.
• Metformin-associated lactic acidosis (MALA) is a rare but potentially life-threatening complication of metformin use, often occurring in patients with kidney and liver conditions, malignancy, or use of certain medications 5.
• Other causes of lactic acidosis include sepsis, fever, diarrhea, vomiting, and acute kidney injury 3, 4, 7.
• The liver plays a major role in removing lactate and hydrogen ions, and abnormalities in aerobic metabolism of lactate by mitochondria in hepatocytes and other cells may contribute to lactic acidosis 7.
• Certain subsets of patients taking metformin are at greater risk of developing lactic acidosis, including those with chronic nephropathy, sepsis, and gastrointestinal fluid loss 3, 4, 6.

Risk Factors

• Patients with type 2 diabetes mellitus taking metformin are at risk of developing lactic acidosis, particularly those with kidney and liver conditions, malignancy, or use of certain medications 3, 4, 5, 6.
• Use of renin-angiotensin system blockade in patients with type 2 diabetes increases the risk of kidney dysfunction and lactic acidosis 4.
• Poor oral intake, excessive antibiotic use, and acute kidney injury can also increase the risk of lactic acidosis in patients taking metformin 5.

Treatment and Prevention

• Prompt recognition and treatment of the underlying causes of lactic acidosis remain the cornerstone of treatment 7.
• Aggressive treatment strategies, including hemodialysis, peritoneal dialysis, continuous bicarbonate infusion, and tight glucose control, may be necessary to improve outcomes in patients with metformin-associated lactic acidosis 4, 6.
• Patients receiving metformin should be counseled to stop metformin and seek medical care in the setting of illnesses, particularly those that increase the risk of kidney dysfunction 4.