What are the potential causes and further evaluation steps for a patient with significant unplanned weight loss, low vitamin B12 (B12) levels despite oral supplementation, daily bloating, exhaustion, and laboratory results showing mildly low protein, globulin, and white cell count (WCC), high ferritin, and vitamin D levels, with a planned investigation for celiac disease?

Malabsorption Workup Beyond Celiac Disease

Your clinical suspicion of malabsorption is well-founded, and while celiac disease testing is essential, this presentation—particularly the failure to respond to oral B12 supplementation despite adequate dietary intake—strongly suggests you need to cast a wider diagnostic net.

Key Additional Laboratory Tests to Order

Essential Malabsorption Screening

Check fecal calprotectin or fecal elastase to evaluate for inflammatory bowel disease (particularly Crohn's disease) and pancreatic insufficiency, as both can present with weight loss, malabsorption, and B12 deficiency despite normal bowel movements 1. Crohn's disease with ileal involvement causes B12 malabsorption even without resection, and up to 40% of patients have B12 deficiency 1, 2.

Measure active B12 (holotranscobalamin) and methylmalonic acid (MMA) rather than relying solely on total serum B12 3. Your patient's failure to respond to 12 months of oral B12 supplementation is highly suspicious for true malabsorption rather than dietary insufficiency 3. MMA >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity and will identify the additional 5-10% of patients with functional deficiency missed by serum B12 alone 3.

Specific Autoimmune and Malabsorptive Conditions

Test for pernicious anemia/autoimmune gastritis with intrinsic factor antibodies and gastric parietal cell antibodies 3, 4. Early atrophic gastritis affecting the gastric body impairs B12 absorption and can present before frank pernicious anemia develops 3. Importantly, 12-20% of celiac patients have low B12 without concurrent pernicious anemia 5, 6.

Check thyroid function (TSH, free T4, TPO antibodies) as autoimmune thyroid disease clusters with other autoimmune conditions and has a 28-68% prevalence of B12 deficiency 3. The fatigue may be multifactorial, and subclinical thyroid disease can mask B12 deficiency symptoms 3.

Measure serum gastrin levels if pernicious anemia is suspected, with markedly elevated levels (>1000 pg/mL) indicating the condition 3.

Comprehensive Micronutrient Assessment

Obtain a complete iron panel including serum iron, ferritin, transferrin saturation, and TIBC 1. The high ferritin is paradoxical given the weight loss and malabsorption—in inflammatory conditions, ferritin up to 100 μg/L may still be consistent with iron deficiency, especially with transferrin saturation <20% 1, 7. This could indicate occult inflammation.

Check folate levels concurrently with B12 assessment 7. Folate deficiency commonly coexists with B12 deficiency in malabsorptive conditions, and you must never give folic acid before ensuring adequate B12 treatment, as it can mask B12 deficiency while allowing irreversible neurological damage to progress 2, 7.

Measure vitamin D, calcium, magnesium, and zinc as these are commonly deficient in malabsorptive disorders 1. The high vitamin D you mention is unusual and warrants verification—ensure she's not over-supplementing, as this could indicate poor clinical judgment about supplementation or misunderstanding of her condition.

Check copper and thiamine levels as copper deficiency causes myelopathy mimicking B12 deficiency, and thiamine deficiency causes neurological symptoms including numbness and tingling 3.

Additional Inflammatory and Structural Assessments

Measure CRP and ESR to assess for occult inflammation that could explain the high ferritin and low protein/globulin 1. The mildly low WCC combined with other findings raises concern for chronic inflammatory or autoimmune processes.

Check albumin and prealbumin for more accurate nutritional assessment, though recognize that albumin is an acute phase protein and may be low in active inflammation rather than true malnutrition 1.

Consider small intestinal bacterial overgrowth (SIBO) testing with glucose or lactulose breath testing, as SIBO can cause malabsorption, bloating, and B12 deficiency 1. This is particularly relevant given her daily bloating without other GI symptoms.

Critical Diagnostic Considerations

The B12 Supplementation Failure is Key

The failure to respond to 12 months of oral B12 supplementation is the most telling finding 3, 2. This strongly suggests either:

• True malabsorption (pernicious anemia, ileal disease, SIBO)
• Inadequate dosing (though 12 months should have shown some response)
• Functional B12 deficiency despite "normal" serum levels 3

Celiac disease causes B12 deficiency in 12-41% of untreated patients, and this often normalizes on a gluten-free diet alone 5, 6, 8. However, 30% of celiac patients on long-term gluten-free diets with good compliance still have B12 deficiency 8.

The Neurological Symptoms Demand Urgency

The tingling symptoms represent neurological involvement and require aggressive evaluation and treatment 2. Neurological symptoms from B12 deficiency can become irreversible if untreated, and they often present before hematologic changes 3, 2.

If MMA confirms functional B12 deficiency, switch to intramuscular B12 immediately rather than continuing oral supplementation 2. For neurological involvement, the protocol is hydroxocobalamin 1 mg IM on alternate days until no further improvement, then maintenance every 2 months for life 2.

Practical Testing Algorithm

1. First-tier labs (order now with celiac panel):

   • Active B12 (holotranscobalamin) and MMA
   • Intrinsic factor antibodies and gastric parietal cell antibodies
   • Complete iron panel (iron, ferritin, TIBC, transferrin saturation)
   • Folate, vitamin D (verify level), magnesium, zinc
   • TSH, free T4, TPO antibodies
   • CRP, ESR
   • Fecal calprotectin

2. Second-tier labs (based on initial results):

   • Gastrin level if pernicious anemia suspected
   • Copper and thiamine if neurological symptoms persist
   • SIBO breath testing if bloating predominates
   • Fecal elastase if pancreatic insufficiency suspected

3. Consider endoscopy with gastric and duodenal biopsies regardless of celiac serology results, as this will evaluate for:

   • Celiac disease (duodenal biopsies)
   • Atrophic gastritis (gastric body biopsies)
   • Other small bowel pathology 4, 9

Common Pitfalls to Avoid

Don't rely solely on serum B12 to rule out deficiency—it misses functional deficiency in up to 50% of cases 3. The MMA test is essential here.

Don't assume the high ferritin means adequate iron stores—in inflammatory states, ferritin up to 100 μg/L can still indicate iron deficiency 1.

Don't give folic acid before confirming adequate B12 treatment—this is a critical error that can precipitate irreversible neurological damage 2, 7.

Don't delay switching to IM B12 if oral supplementation has failed for 12 months—this patient has already demonstrated non-response to oral therapy 2.