What are the causes of significant lactic acidosis in an asymptomatic patient?

From the Guidelines

Significant lactic acidosis in an asymptomatic patient is most commonly caused by medications, particularly metformin, which 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.

Causes of Lactic Acidosis

The causes of significant lactic acidosis in asymptomatic patients can be multifactorial, including:

• Medications: metformin, nucleoside reverse transcriptase inhibitors (NRTIs), and propofol
• Occult sepsis
• Malignancy (especially lymphoma and leukemia)
• Liver disease
• Thiamine deficiency
• Certain inborn errors of metabolism

Risk Factors for Metformin-Associated Lactic Acidosis

Metformin-associated lactic acidosis typically occurs with:

• Renal impairment: dose reduction is recommended if the estimated glomerular filtration rate (eGFR) is 30–45 mL/min per 1.73 m²; metformin should be discontinued if the eGFR is less than 30 mL/min per 1.73 m² 1
• Liver dysfunction
• Overdose
• Other risk factors include administration of iodinated contrast agents, situations that could alter renal function, and severe heart failure (left ventricular ejection fraction < 30%) 1

Management

Management involves:

• Identifying and treating the underlying cause
• Discontinuing offending medications
• Supporting organ function
• Considering bicarbonate therapy or renal replacement therapy in severe cases Asymptomatic presentation despite significant acidosis may indicate chronic compensation or gradual onset allowing physiologic adaptation. Any patient with unexplained lactic acidosis requires thorough evaluation, including medication review, infection workup, and assessment for occult malignancy or organ dysfunction, even when symptoms are absent.

From the FDA Drug Label

5 WARNINGS AND PRECAUTIONS

1. 1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis 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 plasma levels were generally >5 mcg/mL Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

The causes of significant lactic acidosis in patients taking metformin 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.
• Drug interactions: The concomitant use of metformin with specific drugs may increase the risk of metformin-associated lactic acidosis, such as those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation 2.
• 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 2. Asymptomatic patients may still be at risk of lactic acidosis, as the onset of metformin-associated lactic acidosis can be subtle.

From the Research

Causes of Significant Lactic Acidosis

• Lactic acidosis is a common condition that can occur in patients with various underlying conditions, including diabetes and chronic kidney disease 3.
• Metformin, a first-line therapy for type 2 diabetes, has been associated with lactic acidosis, but the risk is considered low and acceptable 4, 5.
• The development of lactic acidosis is often related to preventable drug accumulation, and patients should be aware of the importance of discontinuing metformin in certain situations, such as sepsis, fever, diarrhea, or vomiting 4.

Patient Factors Contributing to Lactic Acidosis

• Diabetes is a major risk factor for the development of lactic acidosis, rather than metformin therapy itself 5.
• Acute cardiorespiratory illness, acute renal impairment, and sepsis are common precipitating factors for lactic acidosis 5.
• Age, acute renal failure, and sepsis are associated with increased mortality in patients with lactic acidosis 5.

Asymptomatic Patients with Lactic Acidosis

• Lactic acidosis can occur in asymptomatic patients, and the condition may only be detected through laboratory tests, such as plasma lactate measurements 6.
• Metformin can be safely used in patients with chronic kidney disease stage 3, but regular measurement of plasma lactate is recommended in later stages 6.
• The incidence of lactic acidosis due to metformin in patients with type 2 diabetes mellitus and chronic kidney disease stage 3-5 is considered low, and metformin-induced lactate levels are typically below the parameters of lactic acidosis 7.