Can the anion gap be elevated in the absence of metabolic acidosis?

From the Guidelines

Yes, an anion gap can be elevated without metabolic acidosis, as evidenced by various clinical scenarios where the anion gap increases independently of acid-base status. This is supported by a recent study on ethylene glycol poisoning, which found that some patients with high anion gaps (> 28 mmol/L) did not necessarily have severe acid-base abnormalities 1. The anion gap is calculated as Na+ + K– Cl– HCO−, and a high anion gap can be seen in patients with poor outcomes, but it is not always associated with metabolic acidosis.

Some key points to consider when evaluating an elevated anion gap without metabolic acidosis include:

• Laboratory errors, particularly with sodium, chloride, or bicarbonate measurements
• Hyperalbuminemia, which can elevate the anion gap since albumin is negatively charged
• Certain medications like lithium, carbenicillin, and penicillin, which can contribute to an elevated anion gap without acidosis
• Severe dehydration, which can concentrate unmeasured anions in the blood
• Metabolic alkalosis with concurrent accumulation of organic anions, which can present with a high anion gap despite the absence of acidosis
• Multiple myeloma, which can increase the anion gap through paraprotein production

It is essential to assess the patient's complete clinical picture, including medication history, hydration status, and protein levels, when evaluating a high anion gap without acidosis. The normal anion gap range is typically 8-12 mEq/L, though laboratory reference ranges may vary slightly. As seen in the study on ethylene glycol poisoning, poor outcomes were infrequent when the glycolate concentration is < 12 mmol/L or the anion gap is < 28 mmol/L 1. Therefore, clinicians should consider these non-acidotic causes and evaluate the patient's overall clinical status when encountering an elevated anion gap without metabolic acidosis.

From the Research

Anion Gap and Metabolic Acidosis

• The anion gap can be elevated in the absence of metabolic acidosis, as there is a wide range of normal values (often 8-10 mEq/L) and an increase in anion concentration can be present without an increased anion gap 2.
• The type of retained anion can affect the magnitude of the increase in anion gap relative to change in serum [HCO3(-)], being greater with lactic acidosis compared with ketoacidosis 2.
• High-anion gap hyperchloremic acidosis can mimic diabetic ketoacidosis on initial presentation, and the anion gap can be elevated in the absence of metabolic acidosis 3.

Limitations of Anion Gap Calculation

• The present methods of determining the normal anion gap and change in the anion gap have limitations, and identifying the baseline value for individuals can optimize the use of the calculation in detecting metabolic acidosis 2.
• The anion gap calculation can be affected by perturbations other than changes in acid-base balance, and its effectiveness in identifying mild and more severe disturbances in acid-base balance is limited 2.

Clinical Applications

• The anion gap can provide vital clues that direct the clinician toward the correct diagnosis of high anion gap metabolic acidosis (HAGMA) and can help identify occult acid-base disorders 4.
• The calculation of the anion gap can be used in conjunction with other parameters, such as plasma osmolality and osmolal gap calculations, to guide clinical decision making 4.
• The use of bicarbonate therapy has shown improvement in cases of non-anion gap acidosis, but there is limited data to support its role in high-anion gap hyperchloremic metabolic acidosis 3.