What are the causes and appropriate work‑up for a low serum anion gap combined with a high mean corpuscular hemoglobin?

Diagnostic Approach to Low Anion Gap with High MCH

A low anion gap combined with high mean corpuscular hemoglobin (MCH) suggests two distinct pathophysiologic processes: the low anion gap most commonly reflects hypoalbuminemia, paraproteinemia (especially IgG multiple myeloma), or laboratory error, while the high MCH indicates macrocytic anemia from vitamin B12 or folate deficiency. 1, 2, 3

Initial Laboratory Evaluation

For the Low Anion Gap

• Verify the anion gap calculation and recheck electrolytes to exclude laboratory error or specimen contamination, as these are common causes of spuriously low values 4, 5
• Measure serum albumin immediately, as hypoalbuminemia is the most frequent cause of a true low anion gap, reducing the gap by approximately 2.3 mEq/L for every 1 g/dL decrease below 4.0 g/dL 6
• Calculate the albumin-corrected anion gap using the formula: Anion gap (adjusted) = Anion gap + 2.3 × (4 - albumin in g/dL) 6
• Order serum protein electrophoresis (SPEP) with immunofixation if the corrected anion gap remains low, as paraproteinemia from IgG multiple myeloma can produce anion gaps as low as 2 mEq/L 7, 5
• An anion gap < 3 mEq/L (using ion-selective electrode methodology) should be considered abnormally low and warrants investigation 3, 7

For the High MCH

• Order vitamin B12 and folate levels immediately, as high MCH with macrocytosis most commonly indicates megaloblastic anemia from these deficiencies 2
• Obtain a complete blood count with peripheral smear to confirm elevated MCV and look for hypersegmented neutrophils (≥5 lobes), which are pathognomonic for B12/folate deficiency 2
• Check reticulocyte count to assess bone marrow response; a low or inappropriately normal count indicates impaired erythropoiesis from nutritional deficiency 8, 2
• Measure methylmalonic acid (MMA) and homocysteine if B12 levels are borderline (200-400 pg/mL), as elevated MMA is specific for B12 deficiency while both are elevated in folate deficiency 2

Critical Diagnostic Considerations

Interpreting the Low Anion Gap

• If albumin is low (< 3.5 g/dL), this explains the low anion gap; investigate the underlying cause (liver disease, nephrotic syndrome, malnutrition, chronic inflammation) 6, 5
• If albumin is normal and SPEP shows a monoclonal spike, pursue multiple myeloma workup with urine protein electrophoresis, serum free light chains, skeletal survey, and bone marrow biopsy 7, 5
• If both albumin and SPEP are normal, consider bromide intoxication (rare), extreme hyperkalemia, or persistent laboratory error requiring repeat testing on a new specimen 5

Interpreting the High MCH

• High MCH excludes typical iron deficiency anemia, which produces low MCH; do not empirically treat with iron 1, 2
• If B12 is < 200 pg/mL, begin replacement immediately with intramuscular cyanocobalamin 1000 mcg daily for 1 week, then weekly for 4 weeks, then monthly indefinitely 2
• If folate is < 2 ng/mL, give folic acid 5 mg daily for 2 weeks, then 5 mg weekly for 6 weeks, but never treat folate deficiency alone without first excluding B12 deficiency, as folate can mask B12 deficiency while allowing irreversible neurologic damage (subacute combined degeneration) to progress 2
• If both deficiencies coexist, treat both simultaneously 2

Investigating Underlying Causes

For Hypoalbuminemia

• Assess for liver cirrhosis (check liver function tests, coagulation studies, imaging) 7
• Evaluate for nephrotic syndrome (24-hour urine protein, urine protein-to-creatinine ratio) 7
• Consider chronic inflammatory states or malnutrition 6

For B12 Deficiency

• Obtain anti-intrinsic factor antibodies (most specific for pernicious anemia) 2
• Consider upper endoscopy with gastric biopsy if pernicious anemia is suspected 2
• Evaluate for malabsorption (celiac disease, Crohn's disease, prior gastric surgery) 2
• Review medications (metformin, proton pump inhibitors, H2 blockers) 2

For Folate Deficiency

• Assess dietary intake and alcohol use 2
• Review medications (methotrexate, trimethoprim, phenytoin, sulfasalazine) 2
• Consider malabsorption syndromes 2

Monitoring Response to Treatment

• Repeat CBC after 4-8 weeks to confirm hemoglobin rise of 1-2 g/dL every 2-4 weeks with appropriate vitamin replacement 2, 9
• Reticulocyte count should increase within 1 week of starting B12 or folate therapy, indicating bone marrow response 2
• Recheck anion gap after correcting hypoalbuminemia or treating the underlying paraproteinemia to ensure no masked high anion gap acidosis was present 6

Common Pitfalls to Avoid

• Do not ignore a low anion gap, as it may indicate life-threatening conditions like multiple myeloma or mask a concurrent high anion gap metabolic acidosis 3, 7
• Always correct the anion gap for albumin before determining if it is truly abnormal, as 44% of patients with hypo- or hyperalbuminemia have their anion gap classification change after correction 6
• Never treat folate empirically without checking B12 first, as this can precipitate or worsen neurologic complications of B12 deficiency 2
• Do not assume iron deficiency when MCH is high, as this combination is physiologically incompatible with typical iron deficiency anemia 1, 2
• Consider combined deficiencies, as iron deficiency can coexist with B12/folate deficiency, potentially masking macrocytosis and presenting with normal MCV but still elevated MCH 2