What is Metformin-Associated Lactic Acidosis (MALA)?
Metformin is a medication commonly prescribed as the primary treatment for diabetes, and it also helps prevent the small and large blood vessel complications that can result from this condition. It can also be used for other health issues like polycystic ovary syndrome (PCOS), excess insulin-related obesity, and weight gain caused by antipsychotic medications. The origin of Metformin can be traced back to the French lilac or goat’s rue plant. In Medieval Europe, this plant was used as a herbal remedy. Researchers in the 1920s discovered that it contains guanidine, a compound that lowers blood sugar. Metformin replaced a similar drug, Phenformin, which was removed from the market due to the high risk of a deadly condition called lactic acidosis.
Metformin works in several ways to lower blood sugar levels. It increases the body’s responsiveness to insulin, blocks the production of glucose in the liver, and promotes the absorption of glucose in the cells. However, it may cause side effects. These include symptoms like nausea, vomiting, and diarrhea, more lactate production, slower lactate clearance, and even a risk of lactic acidosis, which is an excessive acid build-up in your body.
A rare, but serious side effect of metformin use is metformin-associated lactic acidosis (MALA). It is a disruption in lactate and hydrogen production in your body that can occur when the pH level drops below 7.35 and the lactate level rises above 5.0 mmol/L. This complication is specifically associated with metformin use or overdose. Depending on the individual and the situation, it could be fatal in up to half of the cases. The fatality rate is even higher when the acidosis and high lactate levels become more severe.
What Causes Metformin-Associated Lactic Acidosis (MALA)?
Having too much metformin, a medication mainly used for treating type 2 diabetes, in your system can lead to a condition called hyperlactatemia, where there’s too much lactate in your blood, and separately, a condition called metabolic acidosis, where your body produces too much acid or your kidneys can’t remove enough acid from your body.
There are two main types of metformin toxicity: incidental MALA and intentional or acute metformin-induced lactic acidosis, also known as MILA. Sometimes, the lines between these can be blurred.
In incidental MALA, another underlying health condition causes metformin to build up in your blood, leading to hyperlactatemia and metabolic acidosis. This can occur when you have other acute or chronic health issues, such as kidney damage, liver or heart failure, shock, severe illness or when you have taken other medications or substances.
On the other hand, MILA is caused by unintentionally or intentionally taking an overdose of metformin, which ends up causing too much lactate and acidosis in your body.
Risk Factors and Frequency for Metformin-Associated Lactic Acidosis (MALA)
Figuring out the actual number of cases of Metformin Associated Lactic Acidosis (MALA) is tough. This is because there’s a wide range of illnesses it includes, from people who are critically ill and just happen to also be taking metformin, to cases where a person overdosed on metformin without any other causes to their illness. Also, data doesn’t show a clear link between levels of metformin, pH, and lactate in the body, causing some people to question whether high lactate and metabolic acidosis (acidic blood) can really be blamed on overdosing on metformin.
Because many cases of MALA take a while to present, levels of metformin might not be measured until treatment has started and already improved the acid levels and lactate in the blood. This could lead to the correlation between the two looking weak.
- Previous studies estimate that MALA happens at a rate of 1 to 9 cases per 100,000 people.
- In cases where a person overdoses on metformin alone, there’s a 9% chance of developing MALA.
- When a person overdoses on multiple substances including metformin, there’s a 0.7% chance of developing MALA.
Signs and Symptoms of Metformin-Associated Lactic Acidosis (MALA)
When checking a patient’s medical history related to the ingestion of metformin, it is vital to find out the dosage taken, the time of ingestion, and any other substances that may have been consumed alongside it. In addition, it’s necessary to identify any other medications used to control blood sugar levels since metformin can be combined with other drugs, like sulfonylureas. Potentially, an intentional overdose of these medications could lead to both metformin-associated lactic acidosis (MALA) and low blood sugar. It’s also important to evaluate the patient’s mental health history and the intent of the ingestion in order to determine whether psychiatric interventions might be necessary after the medical condition is under control.
Patients who’ve had an adverse reaction to metformin often exhibit ambiguous symptoms. They might initially experience side effects related to the digestive system, such as nausea, vomiting, stomach pain, or diarrhea, which are typically associated with metformin use and toxicity. Additionally, they might report shortness of breath, dizziness, feeling light-headed, extreme tiredness, or general discomfort due to acidosis. In more serious cases, the patient might exhibit altered mental status or even lapse into a coma.
A physical exam should start with a general visual assessment in tandem with evaluating the patient’s airway, breathing, and circulation (ABCs). MALA symptoms are non-specific, but they can resemble acidemia from other conditions, which may cause rapid breathing, deep breathing, and rapid heart rate. Severe acidemia can impact the heart’s ability to contract properly and the body’s response to adrenaline, potentially leading to a state of shock and low body temperature.
Testing for Metformin-Associated Lactic Acidosis (MALA)
In some cases, patients with metformin-associated lactic acidosis (MALA) might be critically unwell and unable to share their medical history – this is why extensive laboratory testing is important. Consider MALA as a last resort diagnosis; first, other causes of elevated lactate levels and metabolic acidosis should be excluded.
The initial tests include a point of care blood glucose test, blood gas analysis to evaluate acid-base level, basic metabolic profile to check for electrolyte issues, bicarbonate level, renal function, and lactine level.
If metformin poisoning is suspected based on the patient’s history and lab results, a metformin level test may be ordered. This test is usually done by a reference lab and takes time, so it’s not immediately helpful in figuring out why the patient is unwell. Even then, metformin levels do not always match the severity of MALA. However, this test could be beneficial in determining the actual cause of sudden lactic acidosis, which could help in managing the patient’s care.
Additional lab tests include a complete blood count to check for systemic inflammatory response syndrome (SIRS) and other causes of shock like bleeding, hepatic panel, and coagulation studies to assess liver dysfunction or injury, blood cultures, urinalysis, and urine culture. A CT scan of the abdomen might be useful in distinguishing MALA from other causes, like ischemic gut. Tests should be done for specific drug levels of acetaminophen, salicylate, ethanol, and in suitable cases, ethylene glycol and methanol.
Doctors will conduct an electrocardiogram to assess the heart rhythm and detect any delays in signal conduction that could result from potential electrolyte imbalances or coingestants. A troponin test can also be performed to check for heart damage. Continuous heart monitoring should be initiated. A CT scan of the head may also be needed in patients with altered mental status where the cause is not clear.
Treatment Options for Metformin-Associated Lactic Acidosis (MALA)
There isn’t any antidote available for MALA, a type of lactic acidosis caused by metformin overdose. The primary method of treatment involves supportive care, which focuses on restoring balance in the body, treating any other diseases present, and removing excess metformin from the body where possible. Patients suspected of having overdosed on metformin should be monitored for at least 12 hours for any symptoms or laboratory test results consistent with MALA.
To help remove the drug from the body, activated charcoal, a substance that can bind to certain chemicals, can be given to patients who arrive soon after ingestion. However, this treatment is not suitable if the patient has certain conditions such as a blockage or hole in the bowel, low blood pressure, or slow gut motion. Also, it might not be advisable if the patient has an altered mental state and potentially cannot protect their airway.
If a patient presents with a severely decreased level of consciousness, they might need to be intubated, which means a tube is put down their windpipe to help them breathe. Initial treatment involves a focus on ensuring the airway is open, the patient is breathing, and blood is circulating around the body. If a patient needs to be intubated, the ventilator settings should be adjusted to compensate for the acidity in the blood and the results should be constantly monitored with a test called an arterial blood gas test.
In cases of severe acidosis, a solution containing sodium bicarbonate (baking soda) can be given to help restore the body’s pH balance. While there’s no definitive guideline on when to start this treatment, it’s often considered when the body’s pH is less than 7.20 and if there are heart conditions or instability in the body’s normal functions. However, some studies suggest sodium bicarbonate may not improve the chances of survival in cases of metformin toxicity due to the fact that the acidity exists within the cells which are difficult to reach. Additionally, sodium bicarbonate treatment could lead to excess sodium in the body, increased chloride, increased carbon dioxide production, and changes in blood pressure after bolus injection.
If the patient’s blood pressure drops significantly and doesn’t respond to standard treatments, a medication called methylene blue may be considered. This drug works by inhibiting the production of nitric oxide, a molecule that dilates blood vessels, and helping generate energy in our cells.
In severe cases, hemodialysis or continuous renal replacement therapy may be considered. These are treatments that use a machine to filter waste and excess substances from your blood, just as your kidneys do. Metformin can be partially removed with these treatments due to its characteristics. Special extended sessions may be needed to effectively remove metformin and lactate. Hemodialysis usually stops once the lactate level is below 3 mmol/L and pH rises to 7.35.
In extreme cases where the patient’s heart isn’t working properly and other treatments aren’t helping, extracorporeal membrane oxygenation (ECMO) might be considered. This is a procedure that essentially takes over heart and lung functions to oxygenate and pump blood around the body while these organs recover. This approach can also be used in combination with continuous renal replacement therapy to improve kidney function.
What else can Metformin-Associated Lactic Acidosis (MALA) be?
When doctors are trying to diagnose MALA, which is a condition that can cause high levels of lactic acid and disrupt your body’s pH balance, they also consider other conditions that can cause similar symptoms. MALA is usually diagnosed after other possibilities have been ruled out. Early medical attention is crucial to exclude the potential causes listed below.
Some other medical or toxicological causes that can lead to high levels of lactic acid in the body may include harmful substances affecting the body’s oxygen supply, substances that interfere with energy production, those that hamper the body’s ability to clear lactate, and substances that can cause seizures when taken in excess. They include:
- Cyanide
- Isoniazid
- Antiretroviral drugs
- Linezolid
- Propylene glycol
- Rotenone
- Hydrogen sulfide
- Nalidixic acid
- Salicylate
- Propofol infusion syndrome
- Antiretroviral medications
- Ethylene glycol
- Massive acetaminophen overdose
Non-toxicological causes may encompass conditions like:
- Sepsis
- Shock states
- Status epilepticus (a severe seizure condition)
- Liver failure
- Inborn errors of metabolism (genetic disorders affecting the body’s metabolism)
- Mesenteric ischemia (reduced blood supply to the intestines)
- Diabetic ketoacidosis
- Thiamine deficiency
- Alcoholic ketoacidosis (a complication from heavy drinking)
What to expect with Metformin-Associated Lactic Acidosis (MALA)
The mortality rate for Metformin-Associated Lactic Acidosis (MALA) varies and it often reflects selection bias which means researchers studying it might not have a representative sample. The highest reported mortality rate for MALA can reach up to 30 to 50%, although most rates are lower. The chances of mortality are higher in patients who initially have a pH level less than 7.1 and lactate level higher than 25.
In one study that examined 22 cases of MALA, 83% of patients who had a pH level less than 6.9 and/or lactate levels higher than 25 did not survive. Other studies have found no clear link between Metformin concentration, pH level, and lactate or significant differences in these levels between survivors and non-survivors. However, the outlook for recovery was strongly tied to the presence of kidney, heart, and liver failure, sepsis (a potentially life-threatening condition caused by the body’s response to an infection), and multi-drug overdose.
People who show up at the hospital with altered mental states, comas, severe acidosis (a condition caused by an overproduction of acid in the blood or an excessive loss of bicarbonates from the blood), kidney failure, liver failure, or who need mechanical breathing support are usually admitted to a critical care unit for monitoring. However, patients who don’t show signs of acidosis and don’t exhibit symptoms after being observed for at least 12 hours may be allowed to leave the hospital or cleared for psychiatric evaluation, depending on their situations.
Possible Complications When Diagnosed with Metformin-Associated Lactic Acidosis (MALA)
When someone has a severe case of Metformin-Associated Lactic Acidosis (MALA), ongoing kidney malfunction is a possible outcome. There are documented instances of people continuing to have kidney malfunction even after MALA has been treated. For example, one patient who intentionally took an overdose of the diabetes drug Metformin, came in with slightly elevated creatinine levels, high lactate (a waste product in the blood), and metabolic acidosis (too much acid in the body fluids), and received Continuous Renal Replacement Therapy (CRRT). The lactate levels returned to normal after 24 hours, but kidney function got worse and complete stopping of urine production occurred. The patient needed occasional hemodialysis, a treatment to filter waste and excess water from the blood as an alternative to kidneys, before their kidney function improved.
Common Side Effects:
- Kidney malfunction
- High lactate levels
- Metabolic acidosis
- Need for continuous renal replacement therapy
- Deterioration of kidney function requiring hemodialysis
- Complete stopping of urine production
Preventing Metformin-Associated Lactic Acidosis (MALA)
Doctors may that their patients understand the potential dangers of taking too much of the diabetes medication, metformin, and the importance of sticking to the dosage that has been prescribed. They also need to take extra care with patients with chronic kidney disease; these patients may need smaller doses if they continue metformin treatment. Patients with chronic kidney disease can still take metformin without changing their dose as long as their kidney function, measured by glomerular filtration rate (GFR – which shows how well the kidneys are working), is above a certain level. However, doctors will need to check the patient’s kidney function every 3 to 6 months.
Patients using metformin should avoid drinking alcohol because it can lead to a serious condition called lactic acidosis (MALA – where the body makes too much lactic acid) and liver damage. Doctors may advise stopping metformin use if a patient is experiencing low oxygen level or very low blood pressure, like during a heart attack or shock. They also may advise patients to stop metformin three days after they’ve had a procedure using a dye for X-rays (such as CT scan), and to only restart it after the kidneys have been checked and are working normally. Doctors might also tell patients to stop metformin two days before having general anesthesia for surgery.
Primary care doctors and specialists in hormone disorders (endocrinologists) taking care of these patients should think carefully before prescribing them. They need to take into account other medications the patient is taking, their other medical conditions, their age, and their nutrition status.
