What is the management approach for an adult patient with a low anion gap, normal electrolyte levels, and no underlying medical conditions, such as liver or kidney disease, and who is not taking medications like diuretics or Angiotensin-Converting Enzyme (ACE) inhibitors?

Management of Low Anion Gap in Otherwise Healthy Adults

In an adult patient with an isolated low anion gap (< 3 mEq/L) and otherwise normal laboratory values, the primary action is to verify the result by repeating the measurement, as laboratory error is the most common cause, followed by systematic evaluation for hypoalbuminemia, paraproteinemias (particularly IgG multiple myeloma), and less commonly, bromide intoxication. 1, 2

Understanding the Modern Anion Gap Reference Range

The critical first step is recognizing that current ion-selective electrode methodology has lowered the normal anion gap range from the historical 12 ± 4 mEq/L to 6 ± 3 mEq/L 1, 3. Many clinicians and textbooks still reference outdated values, leading to misinterpretation 3. Based on contemporary data:

• A low anion gap should be defined as < 3 mEq/L 1
• Reference ranges vary by instrument: 5-12 to 10-17 mmol/L depending on analyzer platform 4
• Values < 2 mEq/L are rare and warrant immediate investigation 3

Diagnostic Algorithm

Step 1: Rule Out Laboratory Error

• Repeat the measurement immediately - laboratory error accounts for the majority of low anion gap findings 2
• In one large study of 67,740 consecutive measurements, only 0.8% showed low anion gap, and most were attributed to presumptive laboratory error 2
• Verify specimen integrity and check for contamination or analytical interference 5

Step 2: Evaluate for Hypoalbuminemia

Even with "normal" electrolytes reported, measure serum albumin directly 3, 5:

• Each 1 g/dL decrease in albumin lowers the anion gap by approximately 2.5 mEq/L
• Hypoalbuminemia is one of the two most common true causes of low anion gap 2, 5
• Calculate corrected anion gap: AG(corrected) = AG(measured) + 2.5 × (4.0 - albumin)

Step 3: Screen for Paraproteinemias

Order serum protein electrophoresis (SPEP) with immunofixation 1, 3:

• Multiple myeloma, particularly IgG type, is a critical diagnosis not to miss 3
• Two documented cases showed anion gaps of 2 mmol/L with IgG myeloma 3
• This represents a potentially life-threatening condition masked by the low anion gap

Step 4: Consider Less Common Causes

If the above are negative, evaluate for:

• Hyponatremia - positive correlation exists between sodium concentration and anion gap 2
• Bromide intoxication - historical but still relevant in certain exposures 5
• Extreme hyperkalemia - though this would not present with "normal electrolytes" 5

Clinical Significance and Pitfalls

Critical Warning

A baseline low anion gap can mask concurrent high anion gap metabolic acidosis 1. In patients with conditions that typically elevate the anion gap (renal failure, diabetic ketoacidosis, lactic acidosis), a "normal" anion gap may actually represent a mixed disorder.

Quality Control Implications

The incidence of low anion gap in hospitalized patients is approximately 2.9%, with mean values around 3 mEq/L (range 2-4 mEq/L) 3. If your institution finds high rates of anion gaps < 2 mmol/L or negative values, this signals a quality control issue requiring immediate investigation of electrolyte analyzer calibration 3.

Instrument Variability

Different analyzers produce significantly different anion gap values 4. Reference intervals must be verified for your specific laboratory platform - cobas 8000 versus Architect c16000 systems show statistically significant differences in AG means 4.

Practical Management Approach

For the patient described (normal electrolytes, no underlying disease, not on diuretics/ACE inhibitors):

1. Repeat electrolytes on the same or different analyzer 2
2. Measure serum albumin - if low, this explains the finding and requires evaluation of underlying cause (liver disease, malnutrition, nephrotic syndrome) 3, 2
3. Order SPEP if albumin is normal - screen for occult myeloma 1, 3
4. If all negative, consider the result spurious and monitor with repeat testing in 3-6 months 2

Do not pursue extensive workup beyond these steps unless clinical context suggests specific pathology - the vast majority of isolated low anion gaps in otherwise healthy patients represent analytical variation or unrecognized laboratory error 2.