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 recent study from China where inpatient use of metformin was associated with increased incidence of lactic acidosis 1.
Causes of Lactic Acidosis
The causes of lactic acidosis can be categorized into two main types:
- Type A: Tissue hypoxia, where inadequate oxygen delivery leads to anaerobic metabolism, as seen in:
- Shock
- Severe heart failure
- Respiratory failure
- Severe anemia
- Type B: Medications and underlying conditions that can cause lactic acidosis without hypoxia, including:
- Metformin (especially with kidney dysfunction) 1
- Nucleoside reverse transcriptase inhibitors
- Alcoholism
- Liver disease
- Malignancies
- Certain inborn errors of metabolism
Additional Causes
Other important causes of lactic acidosis include:
- Vigorous exercise, which temporarily increases lactate levels but rarely causes true acidosis in healthy individuals
- Seizures
- Severe infections, particularly sepsis
Treatment and Management
Treatment focuses on addressing the underlying cause, such as:
- Improving tissue perfusion in shock
- Discontinuing offending medications, such as metformin in patients with kidney dysfunction 1
- Treating infections with appropriate antibiotics Understanding the pathophysiology helps clinicians recognize that lactic acidosis is often a marker of serious underlying disease requiring prompt intervention.
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
Lactic acidosis is a complex condition with various causes. The following are some of the key causes:
- Metformin-associated lactic acidosis (MALA) is a rare but serious side effect of metformin therapy for diabetes mellitus 3, 4, 5
- Renal impairment, including renal failure and chronic nephropathy, can increase the risk of lactic acidosis 3, 5
- Tissue hypoxia, such as in circulatory, pulmonary, or hemoglobin transfer disorders, can lead to overproduction of lactic acid 6
- Underutilization of lactic acid, including liver disease, inhibition of gluconeogenesis, pyruvate dehydrogenase (thiamine) deficiency, and uncoupling of oxidative phosphorylation, can also contribute to lactic acidosis 6
- Certain medications, such as metformin, can increase the risk of lactic acidosis, particularly in patients with underlying severe renal and cardiac dysfunction 3, 4, 5, 6
- Other causes of lactic acidosis include cyanide poisoning, certain malignancies, and sepsis 6
Risk Factors
Certain risk factors can increase the likelihood of developing lactic acidosis, including:
- Diabetes mellitus 3, 4, 5
- Renal impairment or failure 3, 5
- Cardiac dysfunction or failure 3, 5
- Liver disease 6
- Certain medications, such as metformin 3, 4, 5, 6
Pathogenesis
The pathogenesis of lactic acidosis involves both hypoxic (type A) and non-hypoxic (type B) causes, which can often coexist 7. The outcome of lactic acidosis is mainly dependent on the cardiovascular effects of acidosis 7.