What are the causes of isolated macrocytosis in a 31‑year‑old woman with coeliac disease, persistent elevated antibodies, joint pain, normal hemoglobin, and normal vitamin B12 and folate levels?

Macrocytosis Without Anemia in Coeliac Disease: Evaluation and Management

In this 31-year-old woman with coeliac disease, persistent elevated antibodies, and isolated macrocytosis despite normal B12/folate, the most likely causes are ongoing gluten ingestion (despite normal serology being possible), alcohol use, liver dysfunction, hypothyroidism, or early myelodysplastic syndrome—and you must systematically exclude these before considering refractory coeliac disease.

Primary Diagnostic Approach

1. Confirm Ongoing Gluten Exposure

The persistent elevated coeliac antibodies strongly suggest continued gluten ingestion, which is the most common cause of non-responsive coeliac disease (accounting for 40-50% of cases) 1. Critical point: Normal B12/folate levels do NOT exclude ongoing gluten exposure as the cause of macrocytosis.

• Immediate actions:
  • Dietitian review with expertise in coeliac disease to identify inadvertent gluten sources 1
  • Consider gluten immunogenic peptide testing in stool/urine (though not widely available in Europe) 1
  • Recognize that coeliac antibodies can remain elevated despite dietary adherence in some cases 1

2. Evaluate Common Non-Megaloblastic Causes

Since B12 and folate are normal, focus on non-megaloblastic macrocytosis causes 2:

Essential laboratory workup:

• Liver function tests (AST, ALT, GGT): Elevated GGT has the highest population attributable fraction (25.0%) for macrocytosis, even higher than B12/folate deficiency 3
• Thyroid function (TSH, free T4): Hypothyroidism is a recognized cause 4
• Alcohol history: Detailed assessment needed—alcohol is the second most common cause of macrocytosis in hospitalized patients 5 and has a 24.6% population attributable fraction 3
• Complete blood count with reticulocyte count: To assess for hemolysis or bone marrow response 2
• Medication review: Specifically for hydroxyurea, methotrexate, azathioprine, or anticonvulsants 2, 4

3. Assess for Functional B12 Deficiency

Despite normal serum B12, functional deficiency can occur 6:

• Methylmalonic acid (MMA): Elevated levels (>300 nmol/L) indicate tissue B12 deficiency even when serum B12 appears normal 6
• Homocysteine: Elevated levels support functional deficiency 6
• This is particularly relevant given the malabsorption context of coeliac disease

4. Consider Coeliac-Specific Complications

Given the persistent elevated antibodies and joint pain:

Evaluate for non-responsive or refractory coeliac disease 1:

• Esophagogastroduodenoscopy with duodenal biopsies: Essential to assess for persistent villous atrophy 1
  • If villous atrophy persists: Consider flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies to distinguish Type 1 vs Type 2 refractory coeliac disease 1
  • Type 2 carries risk for enteropathy-associated T-cell lymphoma (EATL) 1

Other coeliac-related considerations:

• Hyposplenism: Can occur in coeliac disease and may contribute to hematologic abnormalities 7
• Lymphoma risk: Patients with coeliac disease have increased risk, especially T-cell lymphomas 7

5. Rule Out Primary Bone Marrow Disorders

If the above evaluation is unrevealing, consider myelodysplastic syndrome (MDS):

• MDS accounts for 35% of non-megaloblastic macrocytic anemia in some series 8
• Indications for bone marrow biopsy 9:
  • Development of additional cytopenias
  • Progressive macrocytosis
  • Lack of response to treatment of identified causes
  • MCV persistently >110 fL without clear cause
• In unexplained macrocytosis, 11.6% develop primary bone marrow disorders over median 4-year follow-up 9

Clinical Algorithm

Step 1: Comprehensive dietary review + liver function + thyroid function + alcohol assessment + medication review

Step 2: If above normal → Check MMA and homocysteine for functional B12 deficiency

Step 3: If persistent symptoms or elevated antibodies → EGD with biopsies to assess mucosal healing

Step 4: If villous atrophy present → Advanced immunophenotyping to exclude refractory coeliac disease Type 2

Step 5: If all negative and macrocytosis persists → Monitor CBC every 6 months; consider bone marrow biopsy if cytopenias develop 9

Critical Pitfalls to Avoid

1. Don't assume normal B12/folate excludes deficiency: Functional deficiency requires metabolite testing 6
2. Don't overlook alcohol: Even "social drinking" can cause macrocytosis without anemia 5, 3
3. Don't ignore elevated GGT: This has stronger association with macrocytosis than vitamin deficiencies 3
4. Don't delay repeat biopsy in symptomatic patients: Persistent villous atrophy despite "normal" serology occurs in 84% of cases 10
5. Don't miss the joint pain significance: Could indicate systemic inflammation, autoimmune overlap, or evolving complications

Follow-Up Strategy

• If gluten exposure confirmed: Intensive dietary counseling, repeat antibodies and CBC in 6 months 11
• If other cause identified: Treat accordingly and recheck CBC in 3-4 months
• If unexplained: CBC every 6 months with low threshold for bone marrow evaluation if cytopenias emerge 9
• Annual monitoring: Should include full blood count, ferritin, folate, B12, calcium, alkaline phosphatase, TSH, glucose, and liver enzymes 10

The combination of young age, coeliac disease with persistent antibodies, and isolated macrocytosis warrants thorough investigation—this is not a benign finding to simply observe.