What is the significance and management of a low anion gap of 5 in a patient, potentially with conditions such as multiple myeloma or lithium toxicity?

Low Anion Gap of 5: Clinical Significance and Management

Immediate Diagnostic Approach

A low anion gap of 5 mEq/L warrants immediate investigation for multiple myeloma, severe lithium toxicity, or laboratory error, as these represent the most clinically significant and potentially life-threatening causes. 1, 2

Understanding the Context

• With modern ion-selective electrode methodology, the normal anion gap range has shifted from 12 ± 4 mEq/L to 6 ± 3 mEq/L, making values < 3 mEq/L definitively low 1
• Your value of 5 mEq/L falls in the lower range of normal but approaches clinical significance, particularly if trending downward or accompanied by concerning clinical features 3
• The central 90% range for decreased anion gaps is 2-4 mmol/L, with values < 2 mmol/L being rare 3

Priority Differential Diagnosis

Life-Threatening Causes to Rule Out First

Multiple Myeloma:

• Check serum protein electrophoresis (SPEP), immunofixation, and serum free light chains immediately 4, 3
• The cationic paraproteins in multiple myeloma directly reduce the anion gap by increasing unmeasured cations 1, 4
• Two documented cases of IgG multiple myeloma presented with anion gaps of 2 mmol/L 3
• This diagnosis is particularly critical as it represents an occult neoplasm that may otherwise go undetected 1

Severe Lithium Toxicity:

• Obtain stat serum lithium level if any history of lithium use or psychiatric medications 2
• Lithium levels > 4 mEq/L can present with reduced or absent anion gap 2
• This represents a medical emergency requiring immediate hemodialysis 2
• In comatose or altered mental status patients, a reduced anion gap serves as an important clinical clue to lithium intoxication 2

Other Common Causes

Hypoalbuminemia:

• Measure serum albumin level, as this is the most common cause of low anion gap 5, 3
• Each 1 g/dL decrease in albumin reduces the anion gap by approximately 2.5 mEq/L 5
• Calculate corrected anion gap: Corrected AG = Observed AG + 2.5 × (4.0 - measured albumin) 5
• Common underlying conditions include liver cirrhosis and nephrotic syndrome 3

Laboratory Error:

• Verify specimen integrity and check for hemolysis, lipemia, or contamination 5
• Extreme hyperkalemia can artifactually lower the anion gap 5
• Consider repeating the test if clinically inconsistent 1

Clinical Management Algorithm

Step 1: Immediate Laboratory Workup

• Serum albumin 5, 3
• Complete metabolic panel (repeat to confirm) 1
• Serum protein electrophoresis with immunofixation 4, 3
• Serum free light chains 4
• Lithium level (if any psychiatric history or unexplained altered mental status) 2

Step 2: Clinical Assessment

• Review medication list specifically for lithium, bromide-containing compounds 2
• Assess for symptoms of multiple myeloma: bone pain, anemia, renal dysfunction, hypercalcemia 4
• Evaluate for signs of chronic liver disease or nephrotic syndrome 3
• Check for altered mental status or encephalopathy 4, 2

Step 3: Risk Stratification

• High risk (requires urgent intervention): Altered mental status, history of lithium use, unexplained anemia with bone pain, renal dysfunction 4, 2
• Moderate risk: Hypoalbuminemia with chronic disease, trending downward anion gap 3
• Low risk: Isolated finding with normal albumin and no concerning features 1

Critical Clinical Pitfalls

Masking of High Anion Gap Acidosis:

• A baseline low anion gap can mask the identification of concurrent high anion gap metabolic acidosis 1
• In patients with hypoalbuminemia who develop lactic acidosis or ketoacidosis, the anion gap may appear falsely normal 1
• Always calculate the corrected anion gap in hypoalbuminemic patients before ruling out metabolic acidosis 5

Delayed Diagnosis:

• Low anion gap is often clinically unrecognized despite being a useful diagnostic tool 1
• In patients with sickle cell disease or other chronic conditions, coexisting multiple myeloma may be missed if low anion gap is ignored 4
• The finding should prompt immediate investigation rather than dismissal as a laboratory curiosity 1

Special Populations

Patients with Chronic Conditions:

• In sickle cell anemia patients with unexplained deterioration, low anion gap may indicate coexisting multiple myeloma 4
• Patients with liver cirrhosis commonly have low anion gaps due to hypoalbuminemia 3
• Nephrotic syndrome patients require corrected anion gap calculations 3

Quality Control Considerations

• Incidence of decreased anion gap in hospitalized patients is approximately 2.9% 3
• If institutional data shows high incidence of anion gaps < 2 mmol/L, investigate laboratory quality control and check for systematic hypoalbuminemia or hyperglobulinemia 3
• Negative anion gaps are extremely rare and should trigger immediate investigation for laboratory error or severe pathology 3