What is the best approach for a patient with normal ferritin (iron storage protein) levels, low total iron, and low iron saturation, considering their demographic and medical history?

Diagnostic Interpretation: Functional Iron Deficiency or Early Absolute Deficiency

This pattern of normal ferritin with low serum iron and low transferrin saturation most commonly represents functional iron deficiency (adequate iron stores but insufficient iron release for erythropoiesis) or early absolute iron deficiency that has not yet depleted ferritin stores, and requires immediate evaluation of inflammatory markers (CRP/ESR) to distinguish between these entities. 1

Understanding the Laboratory Pattern

• Low transferrin saturation (<20%) is the critical finding here, indicating insufficient iron readily available for red blood cell production regardless of ferritin level 1, 2
• Transferrin saturation reflects iron availability for erythropoiesis rather than total body iron stores, making it more clinically relevant than ferritin in this scenario 1
• TSAT is less affected by inflammatory processes than ferritin, making it a more reliable marker when inflammation is present 2, 3
• Normal ferritin does NOT exclude iron deficiency—ferritin is an acute-phase reactant that rises with inflammation, infection, or tissue damage, potentially masking depleted iron stores 1, 3

Immediate Diagnostic Algorithm

Step 1: Check Inflammatory Markers

• Measure CRP and ESR immediately to determine if ferritin is falsely elevated by inflammation 1
• If CRP/ESR are elevated with ferritin 30-100 μg/L and TSAT <20%, this represents mixed iron deficiency (absolute + functional) 1
• If CRP/ESR are elevated with ferritin >100 μg/L and TSAT <20%, this represents anemia of chronic disease (inflammatory iron block) where iron is sequestered in reticuloendothelial cells 1, 3
• If CRP/ESR are normal with TSAT <20%, this represents true absolute iron deficiency despite "normal" ferritin 1

Step 2: Calculate Transferrin Saturation Precisely

• Use the formula: (serum iron × 100) ÷ total iron-binding capacity 1
• TSAT <16-20% confirms iron deficiency (absolute or functional) 1, 4
• TSAT <16% has high sensitivity for iron deficiency requiring treatment 1

Step 3: Consider Soluble Transferrin Receptor (sTfR) if Available

• sTfR is elevated in true iron deficiency even when ferritin and TSAT are discordant 1
• This test is particularly useful when inflammation makes ferritin interpretation difficult 1
• Elevated sTfR confirms real iron deficiency in the presence of inflammation 1

Clinical Context Matters: Adjust Ferritin Thresholds

In Inflammatory Conditions (IBD, CKD, CHF, Cancer)

• The ferritin threshold shifts upward to <100 μg/L to diagnose iron deficiency in these populations 1, 3
• In chronic kidney disease patients, absolute iron deficiency is defined as ferritin <100 ng/mL AND TSAT <20% 1, 3
• Functional iron deficiency occurs when ferritin is 100-700 ng/mL but TSAT remains <20%, indicating adequate stores but insufficient release 1
• In inflammatory states, ferritin up to 100 μg/L may still represent true iron deficiency 1, 3

In Otherwise Healthy Individuals

• Ferritin <15 μg/L has 99% specificity for absolute iron deficiency 1
• Ferritin 15-30 μg/L indicates low body iron stores and generally warrants treatment 1
• Ferritin <45 μg/L provides optimal sensitivity-specificity balance (specificity 0.92) for clinical decision-making 1

Treatment Approach

Initiate Iron Supplementation Immediately

• Start oral iron supplementation without waiting for additional test results 1, 4
• Ferrous sulfate 325 mg daily or ferrous bisglycinate 30-60 mg elemental iron daily 1, 4
• Alternate-day dosing (60 mg every other day) may improve absorption and reduce GI side effects compared to daily dosing 1
• Take on empty stomach for optimal absorption, or with meals if GI symptoms occur 1

For Patients with Chronic Inflammatory Conditions

• Intravenous iron is preferred for patients with CKD, CHF, IBD, or cancer due to impaired oral iron absorption from elevated hepcidin 4, 3
• In hemodialysis patients with ferritin 500-1200 ng/mL but TSAT <25%, IV iron may still improve hemoglobin despite elevated ferritin 5, 1
• When distinguishing functional iron deficiency from inflammatory iron block is unclear, administer weekly IV iron (50-125 mg) for 8-10 doses; lack of response indicates inflammatory block 1

Investigation for Underlying Cause

Screen for Common Causes

• Check tissue transglutaminase antibodies (tTG) for celiac disease, present in 3-5% of iron deficiency cases 1
• Test for H. pylori non-invasively (stool antigen or urea breath test) 1
• Assess menstrual blood loss history in premenopausal women (most common cause) 1
• Evaluate for GI blood loss, NSAID use, or dietary inadequacy 4

When to Pursue GI Evaluation

• Age ≥50 years requires GI evaluation due to higher risk of malignancy 1, 6
• New or worsening GI symptoms (abdominal pain, change in bowel habits, blood in stool) require urgent evaluation 1
• Failure to respond to adequate oral iron therapy after 8-10 weeks mandates GI investigation 1
• For premenopausal women without red flags, GI investigation is not mandatory unless specific risk factors present 1

Follow-Up and Monitoring

• Repeat CBC and ferritin in 8-10 weeks to assess response to treatment 1
• Expect hemoglobin increase of 1-2 g/dL (10-20 g/L) within one month if treatment is effective 6
• Target ferritin >100 ng/mL to restore iron stores and prevent recurrence 1
• If no improvement, consider malabsorption, non-compliance, ongoing blood loss, or need for IV iron 1
• For high-risk populations (menstruating females, vegetarians, athletes), screen ferritin every 6-12 months 1

Critical Pitfalls to Avoid

• Do not assume normal ferritin excludes iron deficiency—TSAT is the key parameter for assessing iron availability 1, 2
• Do not overlook inflammation as a cause of falsely elevated ferritin masking true iron deficiency 3, 7
• Do not continue daily iron supplementation once ferritin normalizes, as this is potentially harmful 1
• Do not perform extensive GI investigation in young, asymptomatic premenopausal women with heavy menses (yield 0-6.5%) 1
• In CKD patients receiving ESAs, avoid IV iron when ferritin >500 ng/mL without clear evidence of functional iron deficiency 1