What is the anion gap and how is it used in clinical medicine?

Anion Gap: Definition and Clinical Application

The anion gap is a calculated value that represents the difference between measured cations and anions in serum, calculated as Na+ + K+ - Cl- - HCO3-, with a normal range of 3-12 mmol/L using modern ion-selective electrode methods. 1, 2, 3

Calculation and Normal Values

• Calculate the anion gap using the formula: Na+ + K+ - Cl- - HCO3- 1
• The reference range is 5-12 mmol/L when using modern ion-selective electrode techniques, significantly lower than the outdated range of 8-16 mmol/L that many clinicians still incorrectly reference 3
• If potassium is not included in the calculation, add 4 mmol/L to the result; if unclear whether potassium was included, add 2 mmol/L 4
• The anion gap approximates the difference between unmeasured anions (primarily albumin, phosphate, sulfate, and organic acids) and unmeasured cations (calcium, magnesium, potassium) 2, 3

Primary Clinical Utility

• The anion gap divides metabolic acidoses into two critical categories: high anion gap metabolic acidosis (HAGMA) and normal anion gap (hyperchloremic) metabolic acidosis, which immediately narrows the differential diagnosis 2, 5
• An elevated anion gap typically indicates accumulation of unmeasured anions such as lactate, ketoacids, uremic acids, or toxic alcohols 2, 6
• The anion gap is particularly valuable as a surrogate marker for glycolate concentration in ethylene glycol poisoning, where it correlates linearly with glycolate levels and clinical outcomes 4, 1

Clinical Decision Thresholds

Critical Elevations Requiring Immediate Action

• Anion gap >27 mmol/L with suspected ethylene glycol poisoning mandates immediate hemodialysis (strong recommendation from the American College of Critical Care) 4, 1
• Anion gap 23-27 mmol/L with suspected ethylene glycol poisoning warrants consideration of hemodialysis (weak recommendation) 4, 1
• Mortality in ethylene glycol poisoning increases substantially when anion gap exceeds 28 mmol/L, with mortality of 20.4% compared to 3.6% when anion gap is ≤28 mmol/L 4

Moderate Elevations

• Anion gap >24 mmol/L strongly suggests metabolic acidosis and warrants immediate investigation 3
• The mean anion gap in hospitalized patients with elevated values is 16 mmol/L (central 90% range: 13-20 mmol/L), lower than historically reported 3
• Values exceeding 24 mmol/L are rare and should prompt verification of laboratory quality control 3

Diagnostic Approach to Elevated Anion Gap

Immediate Laboratory Workup

• Obtain arterial blood gases to confirm metabolic acidosis (check pH <7.35 and HCO3- <22 mEq/L) 1
• Measure plasma glucose, serum ketones, urine ketones, blood urea nitrogen/creatinine, complete metabolic panel, and lactate 1
• Calculate serum osmolality and osmolal gap to evaluate for toxic alcohol ingestion 2
• Check complete blood count and urinalysis 1
• Obtain bacterial cultures (blood, urine, throat) if infection is suspected as a precipitating factor 1

Common Causes by Anion Gap Range

Anion gap 13-20 mmol/L:

• Diabetic ketoacidosis (typically with glucose >250 mg/dL, pH <7.3, bicarbonate <15 mEq/L) 1
• Lactic acidosis from sepsis, shock, or tissue hypoxia 1
• Chronic renal failure (uremic acidosis) 3
• Early stages of toxic ingestions 1

Anion gap >20 mmol/L:

• Severe diabetic ketoacidosis 1
• Severe lactic acidosis 1
• Toxic alcohol ingestion (ethylene glycol, methanol) 4, 1
• Advanced chronic kidney disease 3
• Salicylate toxicity 6

Important Corrections and Adjustments

Hypoalbuminemia Correction

• The anion gap decreases by approximately 2.5 mmol/L for every 1 g/dL decrease in albumin below 4 g/dL, which can mask an elevated anion gap 2, 3
• Calculate corrected anion gap in hypoalbuminemic patients to avoid missing occult metabolic acidosis 2, 7

Factors That Falsely Alter Anion Gap

Overestimation of anion gap:

• Concomitant acute kidney injury 4
• Ketoacidosis 4
• Hyperphosphatemia 1

Underestimation of anion gap:

• Hypoalbuminemia (most common) 4, 2
• Lithium or barium ingestion 4, 1
• Severe hyperglycemia 2
• Hyperlipidemia causing pseudohyponatremia 3

Delta Gap Analysis

• Calculate delta gap as: (change in anion gap) ÷ (change in bicarbonate) to identify mixed acid-base disorders 5
• Delta ratio of 1:1 indicates uncomplicated high anion gap acidosis 5
• Delta ratio <1:1 suggests combined high anion gap and normal anion gap acidosis 5
• Delta ratio >2:1 indicates combined metabolic alkalosis with high anion gap acidosis 5

Low or Negative Anion Gap

• Anion gap <3 mmol/L or negative values are rare and warrant investigation for laboratory error, specimen contamination, or specific clinical conditions 3, 7
• Common causes include severe hypoalbuminemia, liver cirrhosis, nephrotic syndrome, and paraproteinemias (IgG multiple myeloma) 3, 6, 7
• Less common causes include bromide intoxication, extreme hyperkalemia, hypercalcemia, hypermagnesemia, and hyperviscosity syndromes 6, 7
• Values <2 mmol/L should prompt immediate verification of electrolyte measurements and consideration of paraproteinemia 3

Critical Pitfalls to Avoid

• Do not rely on the outdated reference range of 8-16 mmol/L, which leads to misinterpretation and missed diagnoses with modern laboratory methods 3
• The anion gap has poor predictive value when used indiscriminately without high pre-test probability of specific disorders 4
• Do not use reported ingested dose alone as an indication for treatment decisions in toxic alcohol poisoning 4
• Remember that certain medications (benzylpenicillin) and minerals prepared as sodium or potassium salts can affect electrolyte measurements 4
• Be aware that glycolate can falsely elevate plasma lactate on some analyzers, potentially confusing the clinical picture 1

Quality Control Application

• In hospitalized patients, the incidence of normal, increased, and decreased anion gaps is approximately 59.5%, 37.6%, and 2.9%, respectively 3
• High incidence of anion gap >24 mmol/L or <2 mmol/L in a patient population should trigger review of laboratory quality control and assessment for hypoalbuminemia or hyperglobulinemia 3