What is the recommended evaluation and treatment approach for a patient with suspected iron deficiency or iron overload, particularly those with symptoms such as fatigue, weakness, or shortness of breath, and a history of anemia, kidney disease, or liver disease?

Full Iron Profile with Interpretation

Components of a Complete Iron Panel

A full iron profile must include plasma iron, transferrin, transferrin saturation, ferritin, CRP, hepcidin, and evaluation of red blood cell morphology to properly assess both iron deficiency and iron overload states 1.

Essential Laboratory Tests

• Serum Iron: Measures circulating iron bound to transferrin 1
• Transferrin (or TIBC): Reflects iron transport capacity; elevated in deficiency, low in overload 1
• Transferrin Saturation (TSAT): Calculated as (serum iron/TIBC) × 100; critical for distinguishing deficiency from overload 1
• Ferritin: Reflects iron stores but is an acute phase reactant, requiring interpretation with CRP 1
• CRP: Essential to identify inflammation that falsely elevates ferritin 1
• Hepcidin: Particularly valuable in critically ill patients and inflammatory states to confirm true iron deficiency 1
• Red Blood Cell Morphology: Identifies microcytic hypochromic cells in deficiency 1

Interpretation Algorithm

Iron Deficiency Pattern

Iron deficiency is diagnosed when ferritin is <45 ng/mL in the absence of inflammation, or when transferrin saturation is <20% 1.

• Ferritin <30 ng/mL: Confirms iron deficiency in non-inflammatory conditions 2
• Ferritin 30-100 ng/mL with TSAT <20%: Suggests combined iron deficiency and anemia of chronic disease (ACD) 1
• Ferritin >100 ng/mL with TSAT <20%: Indicates ACD without true iron deficiency 1
• Hemoglobin <13 g/dL (men) or <12 g/dL (women) with ferritin <45 ng/mL: Confirms iron deficiency anemia requiring full GI evaluation 1

Important caveat: Ferritin is falsely elevated by inflammation, liver disease, malignancy, and kidney disease, making it unreliable as a sole marker in these conditions 1, 3. In inflammatory states, rely more heavily on transferrin saturation and hepcidin levels 1.

Iron Overload Pattern

High transferrin saturation (>45%) combined with low TIBC indicates iron overload, not iron deficiency 4.

• TSAT >45% with elevated ferritin: Pursue genetic testing for HFE mutations (C282Y, H63D) for hereditary hemochromatosis 1, 3
• Ferritin >1000 μg/L: Indicates significant iron burden and increased risk of liver fibrosis; consider liver biopsy if transaminases are elevated 1
• MRI R2 quantification*: Non-invasive method to quantify hepatic, splenic, pancreatic, and cardiac iron when diagnosis is unclear or additional risk factors exist 1

When to Measure

Full iron investigation is mandatory in cases of anemia and persistent major fatigue 1.

Additional indications include:

• Heavy menstrual bleeding, pregnancy, or inflammatory bowel disease 2
• Chronic kidney disease, heart failure, or cancer 2
• Symptoms of iron deficiency: fatigue, pica (40-50% of cases), restless legs syndrome (32-40%), exercise intolerance 2
• Elevated liver enzymes with suspected iron overload 3

Treatment Implications Based on Results

For Iron Deficiency

• Oral iron (ferrous sulfate 325 mg daily or alternate days): First-line for most patients 2, 1
• Intravenous iron (1 g single dose over 15 minutes using carboxymaltose formulations): Indicated for active IBD, hemoglobin <10 g/dL, oral intolerance, malabsorption, pregnancy (second/third trimester), or critically ill patients with low hepcidin 1, 2
• Recheck iron studies at 8-10 weeks, not earlier, as ferritin remains falsely elevated after IV iron 1

For Iron Overload

• Phlebotomy (venesection): Treatment of choice for hemochromatosis and iron overload without anemia 1, 4
• Iron chelation (deferasirox): Reserved for transfusion-associated iron overload in hematologic diseases where phlebotomy is contraindicated 1, 5
• Monitor for end-organ damage: Assess liver function (AST, ALT), screen for diabetes, evaluate cardiac and endocrine function 4

Critical Pitfalls to Avoid

• Do not rely on ferritin alone in inflammatory conditions, chronic kidney disease, or liver disease—it will be falsely elevated 1, 3
• Do not confuse high TSAT with low TIBC as iron deficiency—this pattern indicates iron overload requiring hemochromatosis evaluation 4
• Do not check iron studies within 8-10 weeks of IV iron administration—ferritin will be artificially elevated 1
• Do not use a ferritin threshold of <15 ng/mL—this misses 41% of iron deficiency cases; use <45 ng/mL instead 1
• In premenopausal women with mild symptoms, consider empiric iron supplementation before invasive endoscopy, but men and postmenopausal women require bidirectional endoscopy 1