In a patient with serum iron 33 µg/dL, total iron‑binding capacity 208 µg/dL, transferrin saturation 16 %, ferritin 383.8 ng/mL and HbA1c 6.4 %, what is the most likely type of anemia and how should it be evaluated and managed, including treatment of the pre‑diabetes?

Anemia of Chronic Inflammation with Functional Iron Deficiency

This patient has anemia of chronic inflammation (also called anemia of chronic disease) with functional iron deficiency, characterized by the classic pattern of low transferrin saturation (16%), elevated ferritin (383.8 ng/mL), and low serum iron (33 µg/dL). 1

Understanding the Laboratory Pattern

• The combination of transferrin saturation <20% with ferritin >300 ng/mL is diagnostic of anemia of inflammation 1
• Ferritin is an acute-phase reactant that becomes elevated during inflammatory states, masking true iron deficiency 1, 2
• The elevated ferritin (383.8 ng/mL) indicates either adequate iron stores OR inflammation-driven sequestration of iron in reticuloendothelial macrophages, making it unavailable for erythropoiesis 1, 3
• Low TIBC (208 µg/dL) further confirms inflammation, as TIBC decreases in inflammatory states due to reduced transferrin synthesis 1, 4
• The transferrin saturation of 16% sits exactly at the diagnostic threshold for iron deficiency, indicating inadequate iron delivery to bone marrow despite stored iron 1, 5

Pathophysiology in This Case

• Inflammatory cytokines (TNF-α, IL-6) stimulate hepatic hepcidin production, which blocks intestinal iron absorption and traps iron within macrophages 1
• This creates "functional iron deficiency"—iron exists in stores (reflected by elevated ferritin) but cannot be mobilized for red blood cell production 1, 2
• The HbA1c of 6.4% indicates pre-diabetes, which is independently associated with this exact iron pattern (high ferritin, low transferrin saturation) 6

Mandatory Diagnostic Workup

Measure C-reactive protein immediately to quantify the degree of inflammation and interpret the ferritin level accurately 5

Obtain a complete blood count with:

• Mean corpuscular volume (MCV) to assess for microcytosis 1
• Reticulocyte count to evaluate bone marrow response 1
• Review of white blood cells and platelets to exclude bone marrow disorders 1

Calculate estimated glomerular filtration rate (eGFR) using the MDRD formula based on age, gender, race, and serum creatinine to screen for chronic kidney disease, which commonly causes this iron pattern 5

Screen for gastrointestinal blood loss with fecal occult blood testing, as GI bleeding remains a common cause requiring endoscopic evaluation if positive 5

Consider celiac disease serological testing (tissue transglutaminase antibody), as celiac disease has 3-5% prevalence among patients with iron abnormalities and can cause malabsorption 1, 5

Identifying the Underlying Inflammatory Condition

Search systematically for:

• Chronic kidney disease (check eGFR, urinalysis for proteinuria/hematuria) 1, 5
• Congestive heart failure (clinical examination, BNP if indicated) 1
• Inflammatory bowel disease (history of diarrhea, abdominal pain) 5
• Chronic infection (review systems, imaging if indicated) 1
• Malignancy (age-appropriate cancer screening) 1
• Rheumatologic conditions (ANA, rheumatoid factor if clinically suggested) 1

Iron Repletion Strategy

Intravenous iron is strongly preferred over oral iron in this setting because:

• Elevated hepcidin from inflammation blocks intestinal iron absorption regardless of oral dose 5
• Only 21% of patients with functional iron deficiency respond to oral iron, compared to 65% who respond to IV iron 5
• Oral iron cannot overcome the hepcidin-mediated blockade of iron mobilization 5

Specific indications for IV iron in this patient:

• Transferrin saturation <20% with ferritin >100 ng/mL meets criteria for functional iron deficiency requiring IV therapy 5
• If eGFR <30 mL/min/1.73 m², IV iron is the standard of care 5
• Gastrointestinal intolerance to oral iron (if attempted) mandates IV therapy 5

IV iron formulation options:

• Ferric carboxymaltose: up to 1,000 mg single dose, rapid administration, low hypersensitivity risk 5
• Iron sucrose: up to 200 mg per infusion, no test dose required 1, 5
• Low-molecular-weight iron dextran: high-dose infusion possible but requires test dose 5

Treatment targets:

• Achieve transferrin saturation ≥20% to confirm adequate iron availability for erythropoiesis 5
• Target ferritin ≥100 ng/mL (adjusted upward in inflammation) 5

If IV iron is unavailable and oral iron must be used:

• Prescribe alternate-day dosing (every other day) to avoid hepcidin-mediated blockade 5
• Administer on empty stomach (≥1 hour before or ≥2 hours after meals) 5
• Reduce dose to 50-100 mg elemental iron per administration 5
• However, these strategies will likely fail in the presence of active inflammation 5

Management of Pre-Diabetes (HbA1c 6.4%)

The iron abnormalities and pre-diabetes are pathophysiologically linked—high ferritin and low transferrin saturation are independently associated with pre-diabetes and insulin resistance 6

Lifestyle modification is first-line:

• Medical nutrition therapy targeting weight loss of 7% if overweight 6
• Moderate-intensity physical activity 150 minutes per week 6

Metformin should be considered for patients with HbA1c 6.0-6.4%, especially with additional risk factors (BMI ≥35 kg/m², age <60 years, history of gestational diabetes) 6

Monitor HbA1c every 3-6 months to assess progression and response to intervention 6

Critical Pitfalls to Avoid

• Do not dismiss iron deficiency based on "normal" or elevated ferritin alone—ferritin >300 ng/mL does not exclude functional iron deficiency when transferrin saturation is low 1, 5
• Do not rely on serum iron levels for diagnosis—serum iron has high day-to-day variability and is affected by meals, diurnal changes, and inflammation 5
• Do not prescribe oral iron without first measuring CRP and identifying the inflammatory source—oral iron will fail if inflammation is active 5
• Do not overlook chronic kidney disease—even mild CKD (eGFR 30-60 mL/min/1.73 m²) commonly produces this exact iron pattern and requires nephrology involvement 1, 5
• Do not assume the anemia is solely from iron deficiency—inflammatory cytokines directly suppress erythropoietin production and bone marrow response 1, 3

Monitoring After Treatment

• Recheck complete blood count, iron panel, and CRP at 4-8 weeks after initiating IV iron 5
• If hemoglobin fails to improve despite achieving target iron parameters, consider erythropoiesis-stimulating agents if CKD is present 1
• Continue to address the underlying inflammatory condition, as definitive treatment requires correction of the primary disorder 1, 3