What is the likely diagnosis and recommended evaluation and treatment for a patient with low serum iron, low total iron‑binding capacity (TIBC), and low ferritin?

Anemia of Chronic Disease with Functional Iron Deficiency

The combination of low serum iron, low TIBC, low ferritin, AND low transferrin indicates anemia of chronic disease (ACD) with severe underlying inflammation suppressing both iron stores and transferrin synthesis—this pattern demands immediate investigation for occult malignancy, chronic infection, or advanced chronic kidney disease. 1

Understanding This Atypical Laboratory Pattern

• Low TIBC (or low transferrin) is the critical distinguishing feature that separates this presentation from typical iron deficiency, where TIBC is characteristically elevated. 1, 2
• In classic iron deficiency, the body compensates by increasing transferrin production, raising TIBC to capture more circulating iron; when TIBC is low instead, chronic inflammation is actively suppressing hepatic transferrin synthesis. 1, 3
• Low ferritin in the setting of inflammation is particularly concerning—ferritin is an acute-phase reactant that should be elevated during inflammatory states, so a low value indicates both severe inflammation AND true iron depletion. 1, 4
• This pattern reflects a "double hit": the inflammatory process has both depleted iron stores through sequestration and suppressed the compensatory mechanisms (transferrin production) that normally occur in simple iron deficiency. 1, 2

Immediate Diagnostic Algorithm

Step 1: Confirm Inflammation and Assess Severity

• Measure CRP and ESR immediately—expect markedly elevated values (CRP often >10 mg/L, ESR >30 mm/hr). 1
• Check complete blood count with differential to assess for anemia severity and evaluate for concurrent cytopenias suggesting bone marrow pathology. 1, 3
• Calculate transferrin saturation: TSAT = (serum iron × 100) ÷ TIBC; expect TSAT <20%, confirming iron-deficient erythropoiesis. 1, 3

Step 2: Investigate Life-Threatening Underlying Causes

• Malignancy screening is mandatory in adults, particularly those >50 years or with constitutional symptoms (weight loss, night sweats, fatigue). 1
  • Order age-appropriate cancer screening: colonoscopy for gastrointestinal malignancy, CT chest/abdomen/pelvis if constitutional symptoms present. 1
  • Check stool for occult blood to detect gastrointestinal bleeding. 3
• Assess for chronic kidney disease, which commonly presents with this laboratory pattern when GFR <30 mL/min/1.73m². 1
  • Calculate eGFR using serum creatinine, age, sex, and race. 3
  • Order urinalysis to detect proteinuria or hematuria. 3
  • If eGFR <30 mL/min/1.73m², involve nephrology consultation. 3
• Evaluate for chronic infection or inflammatory conditions: 1
  • Screen for HIV, hepatitis B/C in at-risk populations.
  • Consider tuberculosis screening (QuantiFERON or PPD) if risk factors present.
  • Evaluate for inflammatory bowel disease if gastrointestinal symptoms exist. 1
  • Check rheumatologic markers (ANA, RF) if joint symptoms or rash present.

Step 3: Additional Targeted Testing

• Screen for celiac disease with tissue transglutaminase antibodies—present in 3–5% of iron deficiency cases and can cause treatment failure. 1, 4
• Test for Helicobacter pylori non-invasively (stool antigen or urea breath test). 1
• In hemodialysis patients, low TIBC <250 mg/dL is associated with protein-energy wasting, inflammation, and significantly increased mortality risk (hazard ratio 1.75 for TIBC <150 mg/dL). 5

Critical Diagnostic Pitfall

Do not mistake this pattern for simple iron deficiency. The low TIBC distinguishes ACD from iron deficiency anemia, where TIBC is elevated (typically >350 μg/dL). 3, 2, 6 In one study of hospitalized patients with iron-binding saturation ≤15%, only 3% of those with TIBC ≤250 μg/dL had true iron deficiency, whereas 54% with TIBC ≥350 μg/dL had iron deficiency. 6 Low TIBC signals chronic disease, not simple deficiency. 2, 6

Treatment Algorithm

Immediate Management

• Intravenous iron is the preferred route because it bypasses hepcidin-mediated blockade of intestinal iron absorption that occurs in inflammatory states. 1
• Administer ferric carboxymaltose, iron sucrose, or low-molecular-weight iron dextran as first-line therapy. 1
• Target TSAT ≥20% and ferritin ≥100 ng/mL after iron repletion. 1, 3

When to Add Erythropoiesis-Stimulating Agents

• If no hematologic response occurs after 4–8 weeks of IV iron (hemoglobin rise <1–2 g/dL), consider ESAs with continued iron supplementation, particularly if CKD or heart failure is present. 1, 7
• When ESAs are combined with iron, IV iron yields 73% hemoglobin response rate versus 45% with oral iron. 1
• ESAs require ongoing iron supplementation throughout therapy to optimize dose-response. 1

Oral Iron Is Inappropriate

• Do not use oral iron as first-line therapy in this setting—hepcidin activation in inflammatory states blocks gastrointestinal iron absorption, rendering oral supplementation ineffective. 1
• Oral iron may be considered only after the underlying inflammatory condition is controlled and TIBC normalizes. 1

Monitoring and Follow-Up

• Recheck CBC and iron parameters (ferritin, TSAT) 4–8 weeks after the last IV iron infusion—do not measure within 4 weeks, as circulating iron interferes with assays. 1
• Expected response: hemoglobin should increase by ≥1–2 g/dL within 4–8 weeks of adequate iron therapy. 1, 7
• Reticulocytosis occurs 3–5 days after ferric carboxymaltose administration, indicating bone marrow response. 1
• If ongoing chronic inflammation persists, repeat iron studies every 4–8 weeks to detect and treat iron deficiency before anemia worsens. 1

Prognostic Considerations

• In hemodialysis patients, a decline in TIBC >20 mg/dL over 6 months is independently associated with increased death risk (hazard ratio 1.57). 5
• Low baseline TIBC is associated with protein-energy wasting, inflammation, poor quality of life, and increased mortality. 5
• Coordinate care with nephrology for CKD patients and cardiology for heart failure patients when managing ESA therapy and iron supplementation. 1