What workup should I order for a patient with hypoferritinemia (low iron stores) and a normal Complete Blood Count (CBC)?

Workup for Hypoferritinemia with Normal CBC

In a patient with low ferritin and normal hemoglobin, the workup should be risk-stratified based on age, sex, and symptoms, with men, postmenopausal women, and those with GI symptoms requiring more aggressive investigation than premenopausal women.

Initial Laboratory Assessment

Your patient already has confirmed hypoferritinemia (non-anemic iron deficiency, NAID), so the next steps focus on identifying the underlying cause:

Essential Additional Tests

• Inflammatory markers (CRP or ESR): Critical to interpret ferritin accurately, as ferritin is an acute phase reactant and may be falsely normal despite iron deficiency in inflammatory states 1
• Transferrin saturation: A level <16% supports iron deficiency, though specificity is only 40-50% 1
• Urinalysis or urine microscopy: To exclude urinary tract bleeding as a rare cause 1
• Celiac disease screening: Serologic testing is essential, as celiac disease is found in 3-5% of iron deficiency cases and impairs iron absorption 1

Risk-Stratified Approach to GI Investigation

The British Society of Gastroenterology provides clear guidance that cancer risk in non-anemic iron deficiency is low, but investigation thresholds vary by patient demographics 1:

Low-Risk Patients (Generally No GI Investigation Needed)

• Premenopausal women without GI symptoms or family history of GI pathology 1
• The cause is typically menstrual blood loss, recent pregnancy, or inadequate dietary intake 1
• Treatment with oral iron and monitoring is appropriate 1

High-Risk Patients (Low Threshold for GI Investigation)

Men, postmenopausal women, and those with any of the following should undergo endoscopic evaluation 1:

• GI symptoms (abdominal pain, change in bowel habits, dyspepsia)
• Family history of GI malignancy or inflammatory bowel disease
• Age >45 years (even in premenopausal women, given increasing cancer risk with age) 1

Recommended GI investigations 1:

• Gastroscopy and colonoscopy as first-line investigations
• Small bowel biopsy at time of gastroscopy to screen for celiac disease if not done serologically 1
• CT colonography if colonoscopy not suitable 1

Additional Considerations

When Ferritin Interpretation is Challenging

• If ferritin is 30-45 μg/L with inflammation present, consider GI investigation especially in chronic inflammatory conditions 1
• Ferritin >150 μg/L makes absolute iron deficiency unlikely even with inflammation 1

Other Causes to Evaluate

• Dietary history: Vegetarian/vegan diet, eating disorders, inadequate intake 2, 3
• Medication review: NSAIDs (causing occult GI bleeding), proton pump inhibitors (impairing absorption) 3
• Malabsorption risk factors: History of bariatric surgery, atrophic gastritis 3

Common Pitfalls to Avoid

• Do not rely on fecal occult blood testing - it is insensitive and non-specific for identifying sources of blood loss 1
• Do not order extensive small bowel imaging unless there is transfusion-dependent anemia or visible blood loss 1
• Do not skip celiac screening - it is a high-yield test found positive in 3-5% of cases 1
• Do not assume normal ferritin excludes iron deficiency if inflammatory markers are elevated; use a cutoff of 100 μg/L in inflammatory states 1

Summary Algorithm

1. Check CRP, transferrin saturation, urinalysis, and celiac serology 1
2. If premenopausal woman without alarm features: Treat with oral iron and monitor 1
3. If man, postmenopausal woman, or alarm features present: Proceed to gastroscopy and colonoscopy 1
4. Initiate iron replacement in all cases while investigating 1