How to manage a patient with abnormal iron, ferritin, and transferrin levels?

Management of Abnormal Iron Studies: Low Iron, Elevated Ferritin, Low Transferrin

This patient presents with a pattern suggesting iron overload (elevated ferritin 221 ng/mL) with paradoxically low serum iron (58 μg/dL) and low transferrin (192 mg/dL), which requires immediate evaluation for hemochromatosis and assessment for underlying chronic disease or inflammation. 1

Immediate Diagnostic Steps

Calculate Transferrin Saturation

• First, calculate transferrin saturation (TSAT) using the formula: (serum iron ÷ TIBC) × 100 1
• TIBC can be estimated from transferrin: TIBC (mg/dL) = transferrin (mg/dL) × 1.4-1.5 1
• With iron 58 μg/dL and transferrin 192 mg/dL, estimated TIBC ≈ 268-288 mg/dL, yielding TSAT ≈ 20-22% 1

Interpret the Iron Panel Pattern

This pattern (ferritin >200 ng/mL with borderline TSAT) requires genetic testing for hemochromatosis, particularly HFE gene mutations (C282Y and H63D). 1

• Ferritin >200 μg/L (female) or >300 μg/L (male) with TSAT >45% strongly suggests hemochromatosis 1
• Your patient's TSAT is borderline (≈20-22%), which is less typical for classic hemochromatosis but does not exclude it 1
• Low transferrin (192 mg/dL, below reference 149-313 mg/dL) suggests possible inflammation or chronic disease rather than pure iron overload 1

Differential Diagnosis Algorithm

If TSAT >45%: Suspect Hemochromatosis

• Order HFE genetic testing immediately (C282Y and H63D mutations) 1
• If patient is of non-European origin, consider direct sequencing of HFE and non-HFE genes (HJV, TFR2, CP, SLC40A1) 1
• Check liver transaminases (AST, ALT) and assess for hepatomegaly 1
• If ferritin <1,000 μg/L with normal transaminases and no hepatomegaly, risk of advanced liver fibrosis is very low 1

If TSAT <20% with Elevated Ferritin: Suspect Anemia of Chronic Disease/Inflammation

• This pattern (TSAT <20% with ferritin >300 ng/mL) indicates anemia of inflammation or functional iron deficiency 1
• Check inflammatory markers: CRP, ESR 1
• Evaluate for chronic conditions: chronic kidney disease (serum creatinine, GFR), heart failure (BNP/NT-proBNP), chronic infections, malignancy 1
• Consider soluble transferrin receptor (sTfR) if available: sTfR >5 mg/dL or sTfR/log(ferritin) <1.5 suggests functional iron deficiency 1

If TSAT 20-45% (Borderline): Further Characterization Needed

• Check reticulocyte hemoglobin content (CHr): values <30 pg predict iron-restricted erythropoiesis 1, 2
• Measure complete blood count with reticulocytes to assess for anemia and hemolysis 1
• Check haptoglobin (yours is 72 mg/dL, within normal range 41-333 mg/dL, making hemolysis less likely) 1

Additional Essential Testing

Order the following tests to complete the evaluation: 1

• Liver function tests (AST, ALT, alkaline phosphatase, bilirubin) to assess for hepatic involvement 1
• Serum creatinine and calculated GFR to rule out chronic kidney disease 1
• Complete blood count with MCV and reticulocyte count to characterize any anemia 1
• Fasting glucose or HbA1c (hemochromatosis can cause diabetes) 1

Risk Stratification for Hemochromatosis

If hemochromatosis is confirmed, assess for organ damage: 1

• Cardiac evaluation (ECG and echocardiography) if ferritin is severely elevated or symptoms of heart disease present 1
• Consider cardiac MRI for myocardial iron quantification if conduction disease or contractile dysfunction detected 1
• Evaluate for joint disease (particularly 2nd/3rd metacarpophalangeal joints, ankles, hips) as arthropathy affects 86.5% of hemochromatosis patients 1
• Screen for osteoporosis, as it is common and does not respond uniformly to phlebotomy 1

Management Based on Final Diagnosis

If Hemochromatosis Confirmed (HFE C282Y homozygote or compound heterozygote):

• Initiate therapeutic phlebotomy: remove 500 mL blood weekly until ferritin <50 μg/L and TSAT <50% 1
• Maintenance phlebotomy every 2-4 months to keep ferritin 50-100 μg/L 1
• Monitor liver fibrosis with non-invasive scores (APRI, FIB-4) or transient elastography 1

If Functional Iron Deficiency/Anemia of Chronic Disease:

• Treat underlying condition (heart failure, CKD, inflammation) 1
• Consider intravenous iron if TSAT <20% and ferritin 100-300 ng/mL, particularly in heart failure or CKD 1
• Oral iron is generally ineffective when hepcidin is elevated due to inflammation 1
• Monitor response with CHr, which increases within days of effective iron therapy 2

If Absolute Iron Deficiency (unlikely with your ferritin 221 ng/mL):

• Refer to gastroenterology to rule out GI malignancy as source of blood loss 1
• Oral iron supplementation in divided doses if no GI pathology and adequate absorption 1

Critical Pitfalls to Avoid

• Do not assume normal iron status based on elevated ferritin alone—ferritin is an acute phase reactant and can be falsely elevated in inflammation 1
• Do not delay hemochromatosis genetic testing if TSAT is elevated, as early diagnosis prevents irreversible organ damage 1
• Do not overlook cardiac evaluation in confirmed hemochromatosis with severe iron overload, as cardiac iron deposition causes life-threatening arrhythmias 1
• Do not use oral iron when functional iron deficiency is present (high ferritin, low TSAT), as hepcidin blocks intestinal absorption 1
• Transferrin/log(ferritin) ratio >1.70 can help diagnose iron deficiency when ferritin is 20-100 μg/L, but your ferritin is above this range 3