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 such as metformin, especially in patients with kidney dysfunction 1. The main causes of lactic acidosis can be categorized into two types: Type A, which is caused by tissue hypoxia, and Type B, which is caused by medications and metabolic disorders. Tissue hypoxia can occur in conditions such as shock, severe heart failure, respiratory failure, and severe anemia. Medications such as metformin, especially in patients with kidney dysfunction, can also cause lactic acidosis 1. Other medications that can cause lactic acidosis include nucleoside reverse transcriptase inhibitors, propofol, and alcohols like ethanol and methanol. Some of the key underlying conditions that can contribute to lactic acidosis include:
- Liver disease
- Kidney failure
- Diabetes mellitus
- Sepsis
- Seizures
- Certain cancers Rare genetic disorders affecting mitochondrial function may also lead to lactic acidosis. According to a recent study, 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. In patients with hypovolemic shock, lactate is primarily produced by anaerobic glycolysis and is an indirect marker of cellular hypoxia 1. The treatment of lactic acidosis should focus on addressing the underlying cause, supporting circulation and oxygenation, and in severe cases, may require intravenous bicarbonate therapy to correct the acidosis while the primary issue is being resolved.
From the FDA Drug Label
Metformin hydrochloride, the medicine in metformin hydrochloride tablets, can cause a rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. You have a higher chance of getting lactic acidosis if you:
- have kidney problems.
- have liver problems.
- have congestive heart failure that requires treatment with medicines
- drink a lot of alcohol (very often or short-term "binge" drinking).
- get dehydrated (lose a large amount of body fluids).
- have certain x-ray tests with injectable dyes or contrast agents.
- have surgery
- have a heart attack, severe infection, or stroke.
- are 80 years of age or older and have not had your kidney function tested.
The causes of lactic acidosis include:
- Kidney problems: Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment.
- Liver problems: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis, possibly due to impaired lactate clearance resulting in higher lactate blood levels.
- Congestive heart failure: Requires treatment with medicines and can increase the risk of lactic acidosis.
- Excessive alcohol intake: Potentiates the effect of metformin on lactate metabolism.
- Dehydration: Can happen if you are sick with a fever, vomiting, or diarrhea, or if you sweat a lot with activity or exercise and do not drink enough fluids.
- Certain x-ray tests with injectable dyes or contrast agents: Can lead to an acute decrease in renal function and the occurrence of lactic acidosis.
- Surgery: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment.
- Hypoxic states: Such as acute congestive heart failure, cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia.
- Age 65 or greater: The risk of metformin-associated lactic acidosis increases with the patient's age.
- 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.
- 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). 2 2 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 potentially life-threatening condition, often caused by the accumulation of metformin in the body due to renal impairment or other factors 3, 4, 5.
- Type A lactic acidosis occurs when the body must regenerate ATP without oxygen (tissue hypoxia), often due to circulatory, pulmonary, or hemoglobin transfer disorders 6.
- Type B lactic acidosis involves non-hypoxic causes, such as liver disease, inhibition of gluconeogenesis, pyruvate dehydrogenase (thiamine) deficiency, and uncoupling of oxidative phosphorylation 6.
- Other causes of lactic acidosis include cyanide poisoning, certain malignancies, and the use of certain medications 6.
- Gastrointestinal fluid loss, accompanied by the continued use of an angiotensin-converting enzyme inhibitor, can also contribute to the development of lactic acidosis 3.
Risk Factors
Certain risk factors can increase the likelihood of developing lactic acidosis, including: