From the Guidelines
Lactic acidosis is primarily caused by an imbalance between lactic acid production and clearance in the body, with the most common causes including tissue hypoxia and metabolic disorders, such as those induced by metformin use in patients with risk factors like renal impairment or liver disease 1.
Causes of Lactic Acidosis
The causes of lactic acidosis can be broadly categorized into two types: Type A, which occurs due to tissue hypoxia, and Type B, which occurs without tissue hypoxia. Type A lactic acidosis is seen in conditions such as shock, severe heart failure, sepsis, severe anemia, carbon monoxide poisoning, and intense exercise. On the other hand, Type B lactic acidosis can result from liver disease, medications like metformin 1, nucleoside reverse transcriptase inhibitors, and propofol, alcohol abuse, diabetes, malignancies, and certain inborn errors of metabolism.
Key Factors Contributing to Lactic Acidosis
- Tissue Hypoxia: Conditions leading to inadequate oxygen delivery to tissues, such as shock, severe heart failure, and sepsis, can cause lactic acidosis 1.
- Metformin Use: Particularly in patients with risk factors like significant renal impairment (eGFR < 30 mL/min per 1.73 m²), liver disease, or those at risk for acute kidney injury, hypoxia, or shock 1.
- Liver Disease: Impaired lactate clearance due to liver dysfunction can contribute to lactic acidosis.
- Medications and Toxins: Besides metformin, other medications and substances can induce lactic acidosis, including nucleoside reverse transcriptase inhibitors and propofol.
Management and Prevention
The management of lactic acidosis focuses on addressing the underlying cause, improving tissue oxygenation, and discontinuing offending medications 1. In severe cases, treatment may require sodium bicarbonate administration or dialysis to correct the acid-base imbalance. Early recognition is crucial as severe lactic acidosis can lead to multi-organ dysfunction and has high mortality rates if left untreated. Preventive measures include careful assessment of patients before starting medications like metformin, monitoring renal function, and avoiding high doses of metformin, especially in patients with risk factors for lactic acidosis.
From the FDA Drug Label
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 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. 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) Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. 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 associated with metformin use include:
- Renal impairment: Significant renal impairment increases the risk of metformin accumulation and lactic acidosis.
- Drug interactions: 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.
- 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.
- Hepatic impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis 2, 2, 2.
From the Research
Causes of Lactic Acidosis
- Lactic acidosis can be caused by increased production or decreased removal of L-lactic acid 3
- 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 4
- Metformin, a first-line therapy for type 2 diabetes, can cause lactic acidosis, especially in patients with chronic nephropathy 5, 6, 7
- Lactic acidosis can also be caused by other factors such as sepsis, fever, diarrhea, vomiting, which reduce metformin renal clearance 5
- Biguanide-associated lactic acidosis can occur in diabetic patients with renal insufficiency 7
Pathophysiology
- Lactic acidosis is the most common cause of metabolic acidosis in the critical care setting 3
- The pathophysiology of lactic acidosis involves increased production or decreased removal of L-lactic acid 3
- The liver is a major site of removal of lactate and hydrogen ions, and abnormalities in aerobic metabolism of lactate by mitochondria in hepatocytes and other cells may contribute to lactic acidosis 4