From the Guidelines
Lactic acidosis is primarily caused by tissue hypoxia and metabolic dysfunction, with key triggers including shock, severe anemia, liver failure, kidney disease, and certain medications like metformin, especially in patients with renal impairment. The causes of lactic acidosis can be broadly categorized into two types: type A, resulting from inadequate oxygen delivery to tissues, and type B, occurring despite adequate tissue oxygenation due to underlying diseases or metabolic issues. Common causes of type A lactic acidosis include:
- Shock (septic, cardiogenic, or hypovolemic)
- Severe anemia
- Carbon monoxide poisoning
- Severe hypoxemia Type B lactic acidosis is caused by underlying conditions such as:
- Liver failure
- Kidney disease
- Diabetes mellitus
- Malignancies Medications can also trigger lactic acidosis, particularly:
- Metformin, especially in patients with renal impairment 1
- Nucleoside reverse transcriptase inhibitors
- Propofol
- Alcohols like ethanol and methanol Additionally, certain inborn errors of metabolism affecting mitochondrial function can lead to chronic lactic acidosis. Excessive exercise, seizures, and severe asthma attacks may also precipitate lactic acid buildup through increased metabolic demands and respiratory compromise. It is essential to consider these factors when assessing patients with elevated lactate levels to provide appropriate management and prevent further complications. The use of metformin, for instance, should be carefully evaluated in patients with renal impairment, with consideration of dose reduction or discontinuation if the estimated glomerular filtration rate (eGFR) is below 30 mL/min per 1.73 m², as recommended in recent guidelines 1.
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 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 causes of lactic acidosis (elevated lactate levels) 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.
- Metformin's effect on liver uptake of lactate: Metformin decreases liver uptake of lactate, increasing lactate blood levels and potentially increasing the risk of lactic acidosis, especially in patients at risk 2.
From the Research
Causes of Lactic Acidosis
- Metformin-associated lactic acidosis (MALA) is a severe metabolic failure with high related mortality, often caused by the accumulation of metformin in the body due to reduced renal elimination 3, 4, 5, 6
- Risk factors for MALA include renal impairment, excessive alcohol consumption, and the use of certain medications such as histamine-2 receptor antagonists and ribociclib 6
- Lactic acidosis can also be caused by shock, sepsis, and other conditions that lead to tissue hypoxia and increased lactate production 7
- The use of angiotensin-converting enzyme inhibitors, such as lisinopril, can increase the risk of kidney dysfunction and contribute to the development of lactic acidosis 3
Pathophysiology of Lactic Acidosis
- Metformin inhibits mitochondrial oxidative phosphorylation, leading to a decrease in lactate clearance and an increase in lactate production 6
- The accumulation of lactate in the body leads to a high anion gap metabolic acidosis, which can be life-threatening if left untreated 3, 4, 5
- The pathophysiology of lactic acidosis involves a complex interplay between metabolic, renal, and cardiovascular factors, and requires a comprehensive approach to diagnosis and treatment 6
Diagnosis and Treatment of Lactic Acidosis
- The diagnosis of MALA is suspected in patients who have received metformin and have a high anion gap metabolic acidosis, and is confirmed when lactate exceeds 5 mmol/L 6
- Treatment of MALA involves immediate cessation of metformin, supportive management, and extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy 3, 4, 5, 6
- The use of sodium bicarbonate in treating lactic acidosis from shock is controversial, and is generally not recommended unless the patient has a severe acidemia with a pH of less than 7.00 7