How should I evaluate and manage an adult with chronically low ferritin but normal hemoglobin (no anemia)?

Management of Chronically Low Ferritin Without Anemia

In adults with chronically low ferritin but normal hemoglobin, you should investigate the underlying cause based on patient demographics and initiate oral iron supplementation to prevent progression to anemia and alleviate symptoms of non-anemic iron deficiency. 1

Understanding Non-Anemic Iron Deficiency (NAID)

Non-anemic iron deficiency represents the initial phase of iron depletion where body iron stores are exhausted (hypoferritinemia) but hemoglobin remains within normal range. 1 This condition is clinically significant because:

• Iron deficiency without anemia can impair quality of life through fatigue, irritability, depression, difficulty concentrating, restless legs syndrome (32-40% prevalence), pica (40-50%), and reduced exercise tolerance. 2
• Ferritin <15 μg/L indicates virtually absent iron stores with 99% specificity for absolute iron deficiency. 1
• Ferritin <30 μg/L generally indicates low body iron stores and warrants treatment consideration. 1, 3

Risk Stratification for Investigation

The threshold for investigating underlying causes depends critically on patient demographics and symptoms:

HIGH-RISK: Mandatory Investigation Required

• All men of any age with low ferritin—menstrual loss is not a factor, so gastrointestinal pathology including malignancy must be excluded. 1
• All postmenopausal women with low ferritin—similar cancer risk profile to men. 1
• Any patient with GI symptoms (abdominal pain, altered bowel habits, weight loss) or family history of GI pathology, regardless of sex or menopausal status. 1

LOW-RISK: Investigation Generally Not Warranted

• Premenopausal women without GI symptoms—the cause is typically menstrual blood loss and/or recent pregnancy. 1
• The overall prevalence of GI malignancy in NAID is low, and cancer risk in iron deficiency without anemia is significantly lower than with anemia. 1

Mandatory Initial Workup for All Patients

Regardless of risk category, perform these baseline investigations:

• Urinalysis or urine microscopy—to exclude renal tract blood loss as a source of iron depletion. 1
• Celiac disease serology (tissue transglutaminase IgA)—found in 3-5% of iron deficiency cases and causes malabsorption. 1
• Complete blood count with indices—to document baseline hemoglobin, MCV, MCH and confirm absence of anemia. 1
• Comprehensive iron studies—ferritin, serum iron, total iron-binding capacity, and transferrin saturation. 1
• C-reactive protein—ferritin is an acute phase reactant; inflammation can mask true iron deficiency with falsely normal ferritin levels. 3, 2

Important Caveat on Ferritin Interpretation

• In inflammatory conditions, ferritin up to 45-50 μg/L may still represent true iron deficiency due to its acute phase properties. 1
• Ferritin >150 μg/L is unlikely to occur with absolute iron deficiency, even with inflammation present. 1
• Transferrin saturation <20% supports iron deficiency when ferritin is equivocal (46-99 μg/L). 1, 4

Treatment Strategy

First-Line: Oral Iron Supplementation

Initiate oral iron therapy for all patients with confirmed non-anemic iron deficiency:

• Ferrous sulfate 325 mg daily (contains approximately 65 mg elemental iron) is the standard first-line therapy. 2, 4
• Alternate-day dosing (325 mg every other day) may improve absorption by avoiding hepcidin upregulation and reduces gastrointestinal side effects while maintaining efficacy. 4
• Co-administer with vitamin C (orange juice, ascorbic acid supplement) to enhance non-heme iron absorption. 1
• Avoid tea and coffee within 2 hours of iron intake—polyphenols inhibit iron absorption. 1
• Expected side effects include constipation, nausea, and dyspepsia in approximately 50% of patients. 2, 4

Dietary Counseling

• Increase dietary heme iron sources—red meat, poultry, and seafood have superior bioavailability compared to plant-based iron. 1
• Vegetarian/vegan diets require particular attention—non-heme iron bioavailability is substantially lower. 1
• Current RDA for iron: 18 mg/day (females), 8 mg/day (males) in North America; 14.8 mg/day (females), 8.7 mg/day (males) in the UK. 1

When to Consider Intravenous Iron

Intravenous iron is not first-line for uncomplicated NAID but should be considered in specific circumstances:

• Chronic inflammatory conditions (inflammatory bowel disease, chronic kidney disease, heart failure, cancer)—where hepcidin upregulation impairs oral iron absorption. 1, 2
• Documented oral iron intolerance with significant gastrointestinal side effects preventing adherence. 2, 4
• Malabsorption syndromes (celiac disease, post-bariatric surgery)—where intestinal iron uptake is pathologically impaired. 1, 2
• Ongoing blood loss that cannot be immediately controlled. 2, 4

Monitoring Response to Treatment

• Recheck hemoglobin at 2-4 weeks after initiating oral iron therapy. 1, 4

• An increase of ≥10 g/L hemoglobin within 2 weeks confirms absolute iron deficiency even if baseline iron studies were equivocal. 1

• If no hemoglobin rise after 4 weeks of adequate oral iron, consider: 4

  • Non-adherence to therapy
  • Ongoing blood loss
  • Malabsorption (trial of intravenous iron indicated)
  • Incorrect diagnosis

• Repeat complete iron studies at 8-10 weeks to assess ferritin repletion and confirm adequate response. 3

• Target ferritin ≥30 μg/L for healthy adults; higher targets (≥50-100 μg/L) may be appropriate in chronic inflammatory conditions. 1, 3

Long-Term Management

• Patients with recurrent low ferritin benefit from intermittent oral iron to maintain stores rather than continuous daily supplementation. 3
• Monitor iron studies every 6-12 months in patients at ongoing risk (heavy menstrual bleeding, vegetarian diet, chronic inflammatory conditions). 3
• Do not continue long-term daily iron supplementation once ferritin normalizes—this is potentially harmful and unnecessary. 3

Common Pitfalls to Avoid

• Do not dismiss symptoms as "just fatigue"—non-anemic iron deficiency causes real functional impairment and reduced quality of life. 1, 2
• Do not skip investigation in high-risk groups (men, postmenopausal women)—the cancer risk is significant and warrants endoscopic evaluation. 1
• Do not use ferritin alone in inflammatory states—check CRP and consider transferrin saturation; ferritin up to 45-50 μg/L may still represent deficiency. 1, 3
• Do not prescribe intravenous iron as first-line therapy in uncomplicated cases—oral iron is effective, safer, and more cost-effective. 1, 3
• Do not continue iron supplementation indefinitely once stores are replete—monitor and use intermittent therapy only as needed. 3