What is the appropriate work‑up for a patient with falling hemoglobin, low unsaturated iron‑binding capacity (UIBC) and low total iron‑binding capacity (TIBC) while serum iron and transferrin saturation are normal?

Work-Up for Dropping Hemoglobin with Low UIBC/TIBC but Normal Iron and Transferrin Saturation

This pattern—falling hemoglobin with low TIBC and low UIBC despite normal serum iron and transferrin saturation—strongly suggests anemia of chronic disease (ACD) or chronic inflammation, not iron deficiency, and mandates investigation for underlying chronic inflammatory conditions, malignancy, chronic kidney disease, or malnutrition. 1, 2

Understanding the Laboratory Pattern

Low TIBC (<250 μg/dL) indicates decreased transferrin production, which occurs in chronic inflammation, malnutrition, liver disease, or nephrotic syndrome—not in iron deficiency, where TIBC is characteristically elevated (>350 μg/dL). 2, 3

• Normal transferrin saturation (20–50%) with low TIBC means the limited transferrin present is adequately saturated with iron, arguing against true iron deficiency. 2
• Low UIBC reflects the same underlying pathophysiology as low TIBC: reduced transferrin synthesis due to chronic disease states. 4, 5
• In iron deficiency, the body produces more transferrin to capture available iron, raising TIBC; your patient's low TIBC excludes this mechanism. 2, 3

Common pitfall: Clinicians often misinterpret "normal" serum iron as excluding anemia-related iron problems, but serum iron has high day-to-day variability and poor diagnostic accuracy; ferritin and transferrin saturation are far more reliable. 6

Mandatory Initial Work-Up

Step 1: Measure Serum Ferritin and C-Reactive Protein

Ferritin is the single most important next test because it distinguishes between three scenarios: 7, 1, 2

• Ferritin >100 μg/L: Confirms anemia of chronic disease or inflammation; proceed to investigate underlying chronic inflammatory conditions. 7, 2
• Ferritin <30 μg/L: Indicates combined iron deficiency and chronic disease despite the low TIBC; iron supplementation is warranted. 7, 2
• Ferritin 30–100 μg/L: Suggests functional iron deficiency in the setting of chronic disease; elevated CRP supports inflammatory etiology. 7, 1, 2

C-reactive protein (CRP) confirms the presence of inflammation and helps interpret ferritin, which is an acute-phase reactant and can be falsely elevated during illness or stress. 7, 2

Step 2: Complete Blood Count with Red Cell Indices

• Mean corpuscular volume (MCV) <80 fL: Microcytic anemia suggests iron deficiency, thalassemia, or sideroblastic anemia. 7
• MCV 80–100 fL: Normocytic anemia may be caused by hemorrhage, hemolysis, bone marrow failure, anemia of chronic inflammation, or renal insufficiency. 7
• MCV >100 fL: Macrocytic anemia indicates vitamin B12 or folate deficiency, myelodysplastic syndrome, or drug effects (hydroxyurea, diphenytoin). 7
• Red cell distribution width (RDW): High RDW indicates mixed microcytosis and macrocytosis or iron deficiency. 7

Step 3: Reticulocyte Count (Corrected for Anemia)

The reticulocyte index (RI) distinguishes between decreased RBC production and increased destruction/loss: 7

• Low RI (<1.0): Indicates decreased RBC production, suggesting iron deficiency, vitamin B12/folate deficiency, aplastic anemia, or bone marrow dysfunction. 7
• High RI (>2.0): Indicates normal or increased RBC production, suggesting blood loss or hemolysis. 7

Investigation for Underlying Chronic Conditions

Because low TIBC reflects chronic disease, you must systematically evaluate for the following: 1, 2

Chronic Kidney Disease

• Estimated glomerular filtration rate (eGFR): CKD is associated with anemia prevalence increasing dramatically when GFR <30 mL/min/1.73 m². 1, 6
• Urinalysis: Assess for proteinuria or hematuria. 6
• Serum creatinine, blood urea nitrogen: Evaluate renal function. 7, 6
• Erythropoietin level: Low erythropoietin with GFR <60 mL/min/1.73 m² confirms renal anemia. 7

Malignancy and Chronic Inflammation

• Age-appropriate cancer screening: Mandatory in patients with anemia of chronic disease to rule out malignancy. 1
• Stool guaiac testing: GI bleeding is a common cause requiring endoscopic evaluation if positive. 7, 6
• Endoscopy: Indicated in men and postmenopausal women to exclude malignancy as a source of chronic blood loss. 1
• Inflammatory bowel disease evaluation: Consider if diarrhea, hematochezia, or abdominal symptoms are present. 7, 1

Chronic Heart Failure

• Brain natriuretic peptide (BNP) or NT-proBNP: CHF has a high prevalence of iron deficiency, defined by ferritin <100 μg/L or TSAT <20%. 1
• Echocardiography: If clinical suspicion for heart failure exists. 1

Malnutrition and Liver Disease

• Serum albumin, total protein: Low TIBC is associated with hypoalbuminemia and malnutrition. 8, 4
• Liver function tests: Evaluate for chronic liver disease, which decreases transferrin synthesis. 2

Hemolysis (If Reticulocyte Count Is Elevated)

• Coombs test, haptoglobin, indirect bilirubin, lactate dehydrogenase: Evaluate for hemolytic anemia. 7
• Disseminated intravascular coagulation panel: If clinical suspicion exists. 7

Special Consideration: Functional Iron Deficiency in Chronic Disease

Even with normal transferrin saturation, patients with chronic disease can have functional iron deficiency where iron stores are trapped and unavailable for erythropoiesis due to hepcidin activation. 1

• If ferritin is 30–100 μg/L with elevated CRP: Consider functional iron deficiency; intravenous iron bypasses hepcidin-mediated blockade of intestinal iron absorption. 1
• If ferritin is >100 μg/L but hemoglobin continues to drop: Investigate for erythropoietin deficiency (CKD), bone marrow suppression (malignancy, chemotherapy), or ongoing blood loss. 7, 1

Treatment Algorithm Based on Ferritin Results

Ferritin <30 μg/L (Combined Iron Deficiency and Chronic Disease)

• Oral ferrous sulfate 200 mg three times daily is first-line therapy; expect hemoglobin rise of 2 g/dL after 3–4 weeks. 2
• Failure to respond suggests poor compliance, misdiagnosis, continued blood loss, or malabsorption. 2
• Consider intravenous iron if oral iron is not tolerated, if eGFR <30 mL/min/1.73 m², or if no response after 4–8 weeks. 6

Ferritin 30–100 μg/L with Elevated CRP (Functional Iron Deficiency)

• Intravenous iron (ferric carboxymaltose, iron sucrose, or low-molecular-weight iron dextran) is preferred because it bypasses hepcidin-mediated blockade. 1
• Target ferritin ≥100 ng/mL and TSAT ≥20% after iron repletion. 1, 6

Ferritin >100 μg/L (Anemia of Chronic Disease)

• Treat the underlying chronic condition (CKD, CHF, IBD, malignancy). 1, 2
• Consider erythropoiesis-stimulating agents (ESAs) with continued iron supplementation if CKD or heart failure is present. 1
• Monitor hemoglobin at 4–8 weeks after initiating therapy; repeat iron studies only after 4–8 weeks. 2

Key Caveats

• Do not dismiss iron deficiency based on "normal" serum iron alone: Serum iron has poor diagnostic accuracy and high variability; ferritin and transferrin saturation are far more reliable. 6
• Low TIBC in malnourished patients may erroneously increase transferrin saturation: This can mask true iron deficiency in dialysis or malnourished patients. 4
• Normal TSAT with low serum iron in CKD patients still carries risk for anemia: Even with TSAT ≥20%, low serum iron (<70 μg/dL in men, <60 μg/dL in women) predicts anemia in CKD stage 1–4 patients. 8
• Bone marrow biopsy is appropriate if the cause of anemia remains unclear after extensive work-up, particularly to evaluate for sideroblastic anemia or myelodysplastic syndrome. 7