What are the next steps in evaluating and managing a patient with normal hemoglobin and hematocrit levels, but abnormal iron studies, including a ferritin level of 130, iron percentage of 16, and transferrin level of 230?

Evaluation of Abnormal Iron Studies with Normal Hemoglobin

With a ferritin of 130 ng/mL, transferrin saturation of 16%, and transferrin of 230 mg/dL in the setting of normal hemoglobin and hematocrit, the next step is to calculate the serum iron level and confirm the transferrin saturation, then evaluate for functional iron deficiency or an underlying chronic inflammatory condition that may be masking true iron depletion. 1

Understanding the Current Iron Studies

Your patient presents with a discordant iron panel that requires careful interpretation:

• Ferritin 130 ng/mL appears adequate on the surface, but ferritin is an acute-phase reactant that can be falsely elevated in inflammation, chronic disease, infection, hepatitis, cirrhosis, neoplasia, or arthritis 1
• Transferrin saturation 16% is below the diagnostic threshold of 20%, indicating insufficient iron available for hemoglobin synthesis 2, 1
• Transferrin 230 mg/dL is within normal range (typically 200-360 mg/dL), but the low TSAT suggests functional iron deficiency 1

This pattern—adequate ferritin with low transferrin saturation—suggests either functional iron deficiency in the setting of inflammation/chronic disease, or early absolute iron deficiency where ferritin has not yet dropped due to concurrent inflammation. 2, 1

Next Diagnostic Steps

Immediate Laboratory Tests

• Serum iron level to verify the transferrin saturation calculation (TSAT = [serum iron × 100]/TIBC), as TSAT <20% has high sensitivity for diagnosing absolute or functional iron deficiency 1, 3
• Total iron-binding capacity (TIBC) if not already measured, as TIBC increases when iron stores are depleted 1
• C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) to assess for inflammation that could be elevating ferritin and masking true iron deficiency 2, 1
• Complete metabolic panel including serum creatinine and calculated GFR to rule out chronic kidney disease, which commonly presents with functional iron deficiency 2

Additional Evaluation Based on Clinical Context

• Reticulocyte count to evaluate bone marrow response; a low reticulocyte count with adequate iron, folate, and B12 suggests insufficient erythropoietin production or inflammation 2, 1
• Vitamin B12 and folate levels to exclude concomitant nutritional deficiencies that could impair erythropoiesis 2
• Tissue transglutaminase (TTG) antibodies to screen for celiac disease if iron deficiency is confirmed, as malabsorption can cause persistent iron deficiency 1
• Hemoglobin A1c and fasting glucose if diabetes is suspected, as diabetic nephropathy can cause functional iron deficiency 2

Clinical Reasoning and Interpretation Algorithm

If Inflammation Markers Are Elevated:

Use ferritin <100 ng/mL as the diagnostic threshold for iron deficiency in the presence of chronic inflammation, kidney disease, heart failure, or inflammatory bowel disease. 2, 1 Your patient's ferritin of 130 ng/mL may still represent iron deficiency if significant inflammation is present.

• Consider soluble transferrin receptor (sTfR) testing, which reflects cellular iron deficits and is less affected by inflammation than ferritin 1, 3
• Reticulocyte hemoglobin content (CHr or RET-He) provides direct assessment of functional iron availability to erythropoietic tissue and is less affected by inflammation 1, 4

If Chronic Kidney Disease Is Identified:

• Absolute iron deficiency in CKD is defined as transferrin saturation ≤20% with ferritin ≤100 μg/L in predialysis and peritoneal dialysis patients, or ≤200 μg/L in hemodialysis patients 2
• Your patient meets criteria for iron deficiency in the CKD context with TSAT 16% 2
• Nephrology referral is appropriate for evaluation and management, as iron supplementation strategies differ in CKD 2

If No Inflammation or CKD Is Found:

This represents early absolute iron deficiency with borderline ferritin. 1 The low TSAT indicates insufficient iron for erythropoiesis despite apparently adequate stores.

• Investigate for occult blood loss, particularly gastrointestinal sources in men and postmenopausal women 1, 5
• Consider gastroenterology referral for bidirectional endoscopy to rule out gastrointestinal malignancy as a source of chronic blood loss 2
• Test for H. pylori and celiac disease before proceeding to endoscopy 1

Critical Pitfalls to Avoid

• Do not dismiss iron deficiency based on ferritin alone. Ferritin 130 ng/mL may be falsely reassuring if inflammation is present, as ferritin acts as an acute-phase reactant 2, 1
• Do not ignore the low transferrin saturation. TSAT <20% has high sensitivity for diagnosing iron deficiency and is less affected by inflammation than ferritin 2, 1
• Do not assume dietary insufficiency without investigation. In men and postmenopausal women with confirmed iron deficiency, approximately 62% have gastrointestinal bleeding from lesions requiring further investigation 1
• Do not test iron parameters within 4 weeks of IV iron administration if the patient has received recent iron therapy, as circulating iron interferes with assays and gives falsely elevated results 1

When to Consider Iron Supplementation

Iron therapy is not yet indicated given normal hemoglobin and hematocrit, unless the patient is symptomatic or has a condition requiring optimization of iron stores (e.g., upcoming surgery, chronic heart failure, inflammatory bowel disease). 2

However, if further workup confirms functional iron deficiency in the setting of chronic disease:

• Oral iron supplementation may be initiated with 100-200 mg elemental iron daily, co-administered with vitamin C to enhance absorption 1
• Recheck iron parameters and hemoglobin 4-8 weeks after starting supplementation; hemoglobin should increase by 1-2 g/dL if treatment is effective 1
• Intravenous iron may be preferred in patients with chronic kidney disease, heart failure, or inflammatory bowel disease where oral absorption is impaired 2