What is the recommended diagnostic and treatment approach for a patient with suspected iron deficiency or overload, including the components of a comprehensive iron panel?

Iron Panel: Comprehensive Diagnostic and Management Approach

What to Measure in an Iron Panel

A comprehensive iron panel for evaluating suspected iron deficiency or overload must include plasma iron, transferrin, transferrin saturation, ferritin, CRP, hepcidin, and red blood cell morphology evaluation. 1

Core Components:

• Serum ferritin: The primary screening test for both iron deficiency and iron overload 1, 2

  • <15 μg/L indicates absolute iron deficiency in patients without inflammation 2
  • <30 ng/mL diagnostic threshold in non-inflammatory conditions 3
  • <100 μg/L with transferrin saturation <16% suggests iron deficiency when inflammation is present 2

  • 1000 ng/mL in hemochromatosis patients warrants liver biopsy consideration 1

• Transferrin saturation (serum iron/TIBC × 100): Critical for distinguishing iron overload from deficiency 1, 2

  • <20% indicates iron deficiency 3
  • <16% with ferritin <100 μg/L suggests iron deficiency in inflammatory states 2

  • 45% suggests iron overload and warrants HFE gene testing 2

  • 50% is a contraindication to iron therapy 4

• C-reactive protein (CRP): Essential for interpreting ferritin, as ferritin is an acute phase reactant 1, 2

• Hepcidin levels: Particularly valuable in critically ill patients and for differentiating functional from absolute iron deficiency 1

• Red blood cell morphology: Provides additional diagnostic information about iron status 1

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When to Order an Iron Panel

Full investigation of iron status shall be performed in cases of anemia and persistent major fatigue. 1

Specific Indications:

• Anemia (hemoglobin <13 g/dL in men, <12 g/dL in non-pregnant women) 2
• Symptoms of iron deficiency: fatigue, pica, restless legs syndrome, exercise intolerance, difficulty concentrating 3
• Risk factors for iron deficiency: heavy menstrual bleeding, pregnancy, inflammatory bowel disease, chronic kidney disease, heart failure, cancer 3
• Suspected iron overload: elevated liver enzymes, hepatomegaly, diabetes, joint pain, chronic fatigue 1
• Screening in high-risk populations: pregnant women, children at one year of age 5

Important caveat: Iron screening before 6 months of age is of little value in full-term infants with normal birthweight, as their iron stores meet requirements until this age 4

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Diagnostic Algorithm Based on Iron Panel Results

Iron Deficiency Pathway:

If ferritin <30 ng/mL (or <100 μg/L with transferrin saturation <16% in inflammatory conditions):

• Identify and treat the underlying cause 2
• In men and postmenopausal women: Perform bidirectional endoscopy to evaluate for gastrointestinal bleeding 2
• In all patients: Test for H. pylori and celiac disease 2
• Rule out other causes: hemorrhage, hemolysis, nutritional deficiencies, inherited disorders, renal insufficiency 4

Iron Overload Pathway:

If transferrin saturation >45% and ferritin elevated:

• Order HFE gene testing (C282Y, H63D mutations) 1, 2
• If C282Y homozygous: Diagnosis of HFE-hemochromatosis established 1
  • Ferritin >1000 μg/L, elevated AST, hepatomegaly, or age >40 years: Consider liver biopsy 1
  • Otherwise, proceed directly to phlebotomy 1
• If non-C282Y genotype: Use MRI R2* sequences to quantify hepatic iron concentration 1
  • Assess for secondary causes: metabolic syndrome, alcohol excess, chronic liver disease 1

Anemia of Chronic Disease vs. Iron Deficiency:

If ferritin >100 μg/L and transferrin saturation <16%:

• Likely anemia of chronic disease 2
• Measure soluble transferrin receptor (sTfR): High levels indicate coexisting iron deficiency, normal/low levels confirm pure ACD 2
• Always measure inflammatory markers (ESR, CRP) alongside iron studies 2

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Treatment Approach Based on Iron Panel

For Iron Deficiency:

Oral iron is first-line therapy: ferrous sulfate 325 mg daily or on alternate days. 2, 3

• Monitor response with hemoglobin and red cell indices at 3-month intervals for one year, then after another year 2
• Repeat iron studies 8-10 weeks after initiating treatment, not earlier after IV iron as ferritin levels are falsely elevated 1

Intravenous iron (1 g as single dose over 15 minutes using carbohydrate products) is indicated for: 1

• Oral iron intolerance or poor absorption (celiac disease, post-bariatric surgery) 3
• Chronic inflammatory conditions (CKD, heart failure, IBD, cancer) 1, 3
• Ongoing blood loss 3
• Second and third trimesters of pregnancy 3
• Critically ill anemic patients with low hepcidin levels 1

For Iron Overload:

Phlebotomy is the mainstay of treatment for HFE-hemochromatosis. 1, 2

• Reduces mortality, fibrosis, and improves liver function 2
• Iron chelation therapy reserved for transfusion-associated overload in hematologic diseases or when phlebotomy is not feasible 1

For patients receiving chronic transfusion therapy:

• Screen with MRI (R2, T2*, or R2*) for liver iron content every 1-2 years 1
• Cardiac T2* MRI screening for patients with liver iron content >15 mg/g for ≥2 years, end-organ damage, or cardiac dysfunction 1

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Critical Contraindications and Precautions

Iron therapy is absolutely contraindicated in hemochromatosis and should be withheld when transferrin saturation >50% or ferritin >800 ng/mL. 4

Additional Precautions:

• Active infections: IV iron may be harmful; use with extreme caution 4
• Chronic inflammatory conditions: Standard oral iron may be ineffective due to functional iron deficiency; IV iron or erythropoiesis-stimulating agents may be required 4
• In hemodialysis patients: Withhold IV iron for up to 3 months when transferrin saturation >50% or ferritin >800 ng/mL, then re-measure before resuming 4

Common Pitfall:

Do not rely on C282Y homozygosity alone for hemochromatosis diagnosis—evidence of increased iron stores is required 1. Testing for H63D variant is not necessary for diagnosis 1.