What are the recommended tests and treatment for iron deficiency (Hypoferritinemia)?

Diagnosis of Iron Deficiency (Hypoferritinemia)

Primary Diagnostic Test

Serum ferritin is the most sensitive and specific test for diagnosing iron deficiency and should be your first-line laboratory test. 1

Initial Laboratory Evaluation

Order the following tests simultaneously:

• Complete Blood Count (CBC) with hemoglobin, hematocrit, mean corpuscular volume (MCV), and red cell distribution width (RDW) 2
• Serum ferritin as the primary marker of iron stores 1, 2
• Transferrin saturation (TSAT) calculated as (serum iron/total iron binding capacity) × 100 1, 2
• C-reactive protein (CRP) to identify inflammation that may falsely elevate ferritin 3

Diagnostic Thresholds

Without Inflammation Present

• Ferritin <15 μg/L: 99% specific for iron deficiency—diagnosis confirmed 1, 2
• Ferritin <30 μg/L: Generally indicates low body iron stores 1, 2
• Ferritin <45 μg/L: 92% specific for iron deficiency; warrants gastrointestinal investigation especially with chronic symptoms 1
• Ferritin <50 ng/mL: Recommended threshold regardless of sex in the absence of inflammation 1, 4

With Inflammation or Chronic Disease Present

• Ferritin <100 μg/L should be used as the diagnostic threshold when CRP is elevated or in patients with chronic kidney disease, heart failure, inflammatory bowel disease, malignancy, or hepatic disease 1, 2
• Ferritin acts as an acute-phase reactant and can be falsely elevated despite true iron deficiency 1, 2

Transferrin Saturation

• TSAT <20%: High sensitivity for diagnosing absolute or functional iron deficiency 1, 2
• TSAT is less affected by inflammation than ferritin and reflects iron immediately available for hemoglobin synthesis 1, 2

Interpretation Algorithm

1. If ferritin <15 μg/L: Iron deficiency confirmed—proceed to identify cause and treat 2

2. If ferritin 15-45 μg/L: Add serum iron and TIBC to calculate TSAT; if TSAT <20%, iron deficiency confirmed 2

3. If ferritin 45-100 μg/L with elevated CRP or chronic inflammatory condition: Consider iron deficiency present and investigate further 1, 2

4. If ferritin >100 μg/L: Iron deficiency almost certainly not present unless severe inflammation exists 1

Additional Diagnostic Markers

Red Cell Indices

• MCV <80 fL (microcytosis) suggests iron deficiency but is a late finding 1
• RDW >14% with microcytosis strongly suggests iron deficiency anemia 2
• Microcytosis may be absent in combined deficiencies (e.g., with folate deficiency) 1

Advanced Tests (When Diagnosis Unclear)

• Soluble transferrin receptor (sTfR): Elevated in iron deficiency, less affected by inflammation, but not routinely available 1, 2
• Reticulocyte hemoglobin content (CHr or RET-He): Direct assessment of functional iron availability; requires specialized analyzers 1, 2
• Bone marrow biopsy: Gold standard showing absence of stainable iron, reserved for unclear cases requiring definitive diagnosis 2

Identifying the Underlying Cause

Mandatory Investigations

• Detailed menstrual history in premenopausal women—heavy or prolonged bleeding is the most common cause 1, 5
• Dietary assessment for inadequate iron intake, vegetarian/vegan diet, or eating disorders 1, 3
• Medication review for NSAIDs, aspirin, or anticoagulants causing occult bleeding 1
• Urinalysis to exclude urinary blood loss 1
• Celiac disease screening with tissue transglutaminase (TTG) antibodies—found in 3-5% of iron deficiency cases 1

Gastrointestinal Investigation

In men and postmenopausal women with confirmed iron deficiency, bidirectional endoscopy (upper and lower) is strongly recommended as approximately 62% have gastrointestinal bleeding from lesions requiring investigation, and 9% of patients over 65 have gastrointestinal cancer. 1, 2, 6

• Upper endoscopy with small bowel biopsies to screen for celiac disease should be performed first 1
• Colonoscopy should follow unless upper endoscopy reveals carcinoma or celiac disease, as dual pathology occurs in 10% of cases 1
• In premenopausal women without gastrointestinal symptoms or family history, investigation is generally not warranted initially as menstrual loss is the likely cause 1

Critical Pitfalls to Avoid

• Do not rely solely on hemoglobin and hematocrit—these are late indicators that only become abnormal after iron stores are depleted 2
• Do not ignore inflammation when interpreting ferritin—use ferritin <100 μg/L threshold in inflammatory states 1, 2
• Do not check iron parameters within 4 weeks of IV iron administration—circulating iron interferes with assays causing falsely elevated results 1, 2
• Do not assume dietary insufficiency in men and postmenopausal women—gastrointestinal pathology must be excluded 2, 6
• Do not overlook celiac disease—screen all patients with iron deficiency as it is found in 3-5% of cases 1
• Do not test for hemoglobin electrophoresis before checking iron studies—this prevents unnecessary investigation for thalassemia 1

Monitoring Response to Treatment

• Recheck CBC and iron parameters 4-8 weeks after starting treatment 1, 2
• Hemoglobin should increase by 1-2 g/dL within 4-8 weeks if treatment is effective 1, 2, 6
• If hemoglobin does not increase appropriately, consider malabsorption of oral iron, continued bleeding, or unidentified lesion 6
• For patients with recurrent iron deficiency, repeat basic blood tests every 6-12 months to monitor iron stores 3