What else can be tested for in a patient with elevated C-Reactive Protein (CRP), elevated White Blood Cell (WBC) count, and chronic gastrointestinal blood loss without anemia, despite negative full Gastrointestinal (GI) and stool workups?

Alternative Diagnostic Considerations for Elevated CRP, Elevated WBC, and Chronic GI Blood Loss Without Anemia

In a patient with elevated inflammatory markers and chronic GI blood loss despite negative standard workup, you should immediately test for iron deficiency (ferritin, serum iron, TIBC), celiac disease (tissue transglutaminase antibodies with IgA level), and Helicobacter pylori, as these are the most common occult causes of this presentation. 1, 2

Iron Metabolism Disorders

Check comprehensive iron studies even without anemia present:

• Ferritin levels should be checked in all patients with chronic GI symptoms and elevated inflammatory markers 1
• Note that ferritin is an acute-phase protein and may appear falsely "normal" despite true iron deficiency when inflammation is present 1
• If ferritin is apparently normal but iron deficiency is suspected, obtain serum iron and total iron binding capacity 1
• Iron deficiency can cause GI blood loss and elevated inflammatory markers without anemia - this is a critical pitfall that is frequently missed 1
• Consider a trial of iron replacement if ferritin is below 15-25 µg/L or if there is microcytosis not attributable to other causes 1

Celiac Disease and Malabsorption

Celiac disease is found in 2-3% of patients presenting with iron deficiency and GI symptoms, even without typical GI complaints: 1

• Test for tissue transglutaminase (TTG) antibodies in all patients with unexplained iron deficiency 1
• Critically important: Check IgA levels simultaneously - IgA deficiency is relatively common and causes falsely negative TTG results 1
• If TTG is positive or IgA deficient, refer for endoscopy with small bowel biopsy 1
• Consider biopsy even with negative TTG if clinical suspicion remains high 1
• Ensure patient has not been excluding gluten for at least 6 weeks before testing 1

Helicobacter Pylori and Atrophic Gastritis

Non-bleeding gastric pathology is frequently associated with iron deficiency and elevated inflammatory markers: 2

• In one study, 85% of patients with iron deficiency anemia without GI symptoms had identifiable GI causes, with 51% having non-bleeding conditions 2
• Atrophic gastritis was found in 19 of 71 patients (27%) with iron deficiency but no GI symptoms 2
• H. pylori gastritis was identified in 13 patients (18%) 2
• These conditions cause iron malabsorption rather than overt bleeding, explaining the absence of anemia despite chronic blood loss 2

Hematological Disorders

Consider polycythemia vera and other myeloproliferative disorders:

• Ask specifically about aquagenic pruritus (itching after water contact) - this is characteristic of polycythemia vera 1
• Polycythemia vera can present with elevated WBC and CRP without typical symptoms 1
• Check for night sweats, fevers, and weight loss suggesting lymphoma 1
• Haematological causes account for approximately 2% of cases with elevated inflammatory markers and occult bleeding 1

Small Bowel Pathology Beyond Standard Endoscopy

If the above workup is negative and symptoms persist:

• Small bowel angiodysplasia may require enteroscopy for detection, particularly if transfusion-dependent 1
• Small bowel tumors (lymphoma, leiomyoma) can cause occult bleeding with elevated inflammatory markers 1
• Crohn's disease limited to small bowel may be missed on standard colonoscopy 1, 2
• Meckel's diverticulum should be considered in younger patients 1

Critical Diagnostic Algorithm

Follow this sequence:

1. First-line tests (order immediately): 1, 2

   • Complete iron panel: ferritin, serum iron, TIBC
   • Tissue transglutaminase antibodies with total IgA level
   • H. pylori testing (stool antigen or breath test)
   • Complete blood count with peripheral smear

2. If initial tests negative, proceed to: 1

   • Upper endoscopy with gastric body and antral biopsies (even if prior endoscopy was "normal")
   • Small bowel biopsies during endoscopy
   • Consider capsule endoscopy if transfusion-dependent

3. Consider hematology referral if: 1

   • Persistent unexplained elevated WBC
   • Aquagenic pruritus present
   • Constitutional symptoms (night sweats, fever, weight loss)

Common Pitfalls to Avoid

• Do not accept "normal" ferritin at face value when CRP is elevated - ferritin rises with inflammation and may mask iron deficiency 1
• Do not skip celiac testing even with negative prior GI workup - it is found in 2-3% of these patients 1
• Do not assume prior negative endoscopy rules out gastric pathology - targeted biopsies for H. pylori and atrophic gastritis are essential 2
• Do not overlook IgA deficiency when ordering celiac serology - this causes false negative results 1