Is it necessary to check iron and transferrin (Tf) levels in patients with normal hemoglobin (Hb) levels, especially in those with risk factors for iron deficiency or overload, such as premenopausal women, individuals with chronic kidney disease (CKD), or those with gastrointestinal disorders?

Checking Iron Studies in Patients with Normal Hemoglobin

Yes, iron studies (ferritin and transferrin saturation) should be checked even when hemoglobin is normal in patients with risk factors for iron deficiency, including premenopausal women, chronic kidney disease, heart failure, gastrointestinal disorders, and inflammatory bowel disease. 1, 2

Rationale for Testing Despite Normal Hemoglobin

Iron Deficiency Precedes Anemia

• Absolute iron deficiency (depleted iron stores) develops long before hemoglobin drops, affecting approximately 14% of US adults, while iron-deficiency anemia affects a smaller subset. 2
• Iron deficiency progresses through stages: first depleting iron stores (low ferritin), then causing iron-restricted erythropoiesis (low transferrin saturation), and only finally resulting in anemia. 3, 2
• Nonanemic iron deficiency causes significant symptoms including fatigue, irritability, depression, difficulty concentrating, restless legs syndrome (32-40% of cases), pica (40-50%), dyspnea, and exercise intolerance. 2

High-Risk Populations Require Screening

Premenopausal women:

• Approximately 38% have iron deficiency without anemia, and menstrual blood loss is the most common cause of iron deficiency in high-income countries. 2

Chronic kidney disease:

• Iron deficiency affects 24-85% of CKD patients regardless of hemoglobin level, and both absolute and functional iron deficiency are common. 3, 2
• Iron status should be assessed as part of the initial evaluation of all CKD patients, even those with mild anemia (hemoglobin <110 g/L) who are not receiving therapy. 1
• In stable CKD patients with mild anemia not on treatment, iron assessment should be performed at least yearly. 1

Heart failure:

• Iron deficiency affects 37-61% of heart failure patients and contributes to worsening symptoms even when hemoglobin is normal. 1, 2
• The American Journal of Hematology recommends evaluating for iron deficiency with iron studies in ALL chronic heart failure patients (NYHA II-V), regardless of whether they are anemic. 1

Gastrointestinal disorders and inflammatory bowel disease:

• Iron deficiency affects 13-90% of IBD patients, and finding iron deficiency should prompt careful assessment for gastrointestinal bleeding. 1, 2

Pregnancy:

• Up to 84% of pregnant women develop iron deficiency by the third trimester in high-income countries. 2

Diagnostic Thresholds

Standard Population (Without Inflammation)

• Ferritin <30 ng/mL indicates iron deficiency in individuals without inflammatory conditions. 2
• Transferrin saturation <20% indicates insufficient iron availability for erythropoiesis. 4, 5, 2

CKD-Specific Thresholds (Different from General Population)

Absolute iron deficiency in CKD:

• Transferrin saturation ≤20% AND ferritin ≤100 ng/mL (predialysis/peritoneal dialysis patients) or ≤200 ng/mL (hemodialysis patients). 3

Functional iron deficiency in CKD:

• Transferrin saturation ≤20% with elevated ferritin levels, indicating adequate stores but insufficient mobilization. 3

Heart Failure-Specific Criteria

• Iron deficiency is defined as ferritin <100 ng/mL OR ferritin 100-299 ng/mL with transferrin saturation <20%. 1

Critical Pitfalls in Interpretation

Ferritin as an Acute Phase Reactant

• In inflammatory states (CKD, heart failure, IBD, cancer), ferritin may be falsely elevated despite true iron deficiency, making it unreliable when used alone. 1, 6, 7
• Transferrin saturation becomes the more reliable indicator of functional iron deficiency when inflammation is present. 5, 6
• C-reactive protein should be measured to interpret ferritin accurately in inflammatory conditions. 6

Both Parameters Required

• Neither ferritin nor transferrin saturation alone adequately discriminates iron status—both must be measured together and interpreted with clinical context. 4, 7
• The scenario of ferritin >800 ng/mL with transferrin saturation <20% has become increasingly common in patients with comorbidities, representing functional iron deficiency despite apparent iron overload. 8

Population-Specific Thresholds

• Using general population ferritin cutoffs in CKD, pregnancy, or inflammatory conditions leads to inaccurate diagnoses. 6
• Different disease states require different diagnostic thresholds, as reflected in disease-specific guidelines. 7

Clinical Algorithm for Testing

Test iron studies (ferritin AND transferrin saturation) when:

1. Any symptoms of iron deficiency are present (fatigue, pica, restless legs syndrome, exercise intolerance, difficulty concentrating) regardless of hemoglobin. 2

2. Risk factors exist:

   • Heavy menstrual bleeding 2
   • Pregnancy (especially second/third trimester) 2
   • Chronic kidney disease (all stages—test at initial evaluation and yearly if stable) 1
   • Heart failure (all NYHA classes II-V) 1
   • Inflammatory bowel disease 2
   • Gastrointestinal disorders or NSAID use 2
   • Post-bariatric surgery 2
   • Celiac disease or atrophic gastritis 2

3. Before initiating erythropoiesis-stimulating agents in CKD, as iron deficiency must be corrected first. 1

4. When evaluating unexplained symptoms in high-risk populations, even with normal hemoglobin. 2

Impact on Morbidity and Quality of Life

• Treating nonanemic iron deficiency improves fatigue, exercise tolerance, and quality of life in multiple conditions including heart failure and CKD. 1, 2
• In heart failure patients, correcting iron deficiency (even without anemia) reduces hospitalizations and improves functional capacity. 1
• Waiting until anemia develops to diagnose iron deficiency misses the opportunity for earlier intervention and symptom relief. 2