Research Blog

May 1, 2024

Iron Deficiency Without Anemia

Iron deficiency is the most common mineral deficiency and iron deficiency anemia affects approximately 20% of the world’s population.

Iron deficiency without anemia is even more common.

Iron is an essential element required for several metabolic pathways and is responsible for the delivery of oxygen to organs and body tissues. A deficiency can, therefore, result in a wide range of non-specific symptoms that may not be initially recognized as iron deficiency.

Patients with iron deficiency without anemia may present with unexplained, non-specific symptoms. However, iron studies will usually show low ferritin and low transferrin saturation with a normal hemoglobin concentration.

A reduced ferritin is the most reliable initial marker to diagnose iron deficiency without anemia.

Changes in iron status before the development of anemia may be suggested on a full blood count by falling values for mean cell hemoglobin and mean corpuscular volume and an increased red cell distribution width

Iron deficiency without anemia has been associated with:

  • weakness, fatigue, reduced exercise performance, difficulty in concentrating, and poor work productivity
  • neurocognitive dysfunction including irritability
  • fibromyalgia syndrome
  • restless legs syndrome
  • symptom persistence in patients treated for hypothyroidism
  • poor neurodevelopmental outcomes in infants born to mothers with iron deficiency.

Diagnosing iron deficiency

Iron deficiency can occur secondary to inadequate dietary intake, increased requirements (e.g., pregnancy and breastfeeding), impaired absorption (e.g., coeliac disease, bariatric surgery), or blood loss (e.g. menstrual, blood donation, gastrointestinal).

A drug history should be taken, particularly regarding anticoagulants, over-the-counter non-steroidal anti-inflammatory drugs, and antiplatelet drugs.

The underlying cause of iron deficiency should always be assessed and addressed.

Iron studies in the differential diagnosis of iron deficiency


Iron deficiency without anemia

Iron deficiency anemia

Anemia of chronic disease

Iron deficiency anemia and anemia of chronic disease

Hemoglobin N
MCV N or ↓ N (or mildly ↓)
Serum Ferritin N or ↑ ↓ or N
TIBC N or ↑ ↓ or N N or ↑
Transferrin saturation ↓ or N ↓ or N
Soluble transferrin receptor N or ↑ N

N = normal, ↓ = decreased, ↑ = increased

Ferritin and transferrin thresholds for the diagnosis of iron deficiency

Patients and conditions Ferritin concentration Transferrin saturation
General population <30 microgram/L
Inflammatory states <100 microgram/L <20%
Heart failure <100 microgram/L
<300 microgram/L <20%
Kidney disease <500 microgram/L <30%
 Benefits of correcting iron deficiency
Condition Evidence
Fatigue and neurocognitive dysfunction Improves fatigue in some studies but impact on neurocognitive dysfunction is uncertain
Fibromyalgia Improves symptoms of fibromyalgia, possibly related to the role of iron as a cofactor in neurotransmitter synthesis
Restless legs Small, randomized trials have shown improved symptoms with iron supplementation if the serum ferritin is ≤75 microgram/L
Thyroid disease Case reports describe correction of iron deficiency improving persistent symptoms in patients treated for hypothyroidism with adequate levothyroxine therapy
Heart failure Several randomized clinical trials in patients who have heart failure with reduced ejection fraction and iron deficiency have reported improvements in symptoms and quality of life after intravenous iron therapy
Chronic kidney disease (hemodialysis) Intravenous iron in patients with ferritin <700 microgram/L and transferrin saturation <40% results in less need for erythropoiesis-stimulating drugs, possible cardiovascular benefits and reduced blood transfusion requirements
Inflammatory bowel disease Correction of non-anemic iron deficiency in patients with inflammatory bowel disease may improve quality of life

Iron deficiency should be corrected before and during pregnancy to prevent impaired neurocognitive function (poor memory and slower neural processing) in the child

Iron repletion strategies  

Optimizing nutritional iron intake can be achieved by integrating dietary heme iron and free iron.

Heme iron (liver, red meat, seafood, poultry) has a superior gastrointestinal uptake compared to free iron (plant-based).

Vegetarians can maintain adequate iron intake if a wide variety of non-heme iron is consumed in foods such as whole grains, legumes, nuts, seeds, dried fruits, and green leafy vegetables, but these strategies are unlikely to be sufficient to correct iron deficiency.

Inhibitors of iron absorption (tea, coffee, cocoa, and red wines) should be avoided. This strategy is appropriate for asymptomatic patients who are not at risk of poor absorption.

If parenteral iron supplementation is required, intravenous iron is indicated. There is no role for intramuscular therapy.

The use of intravenous iron should be limited because of its adverse effects, including permanent skin staining, hypophosphatemia and rarely anaphylaxis. Intravenous iron should be avoided if there is active systemic infection to avoid any possibility that iron may promote microbial growth and disrupt immune responses.

The main indications for intravenous iron include:

  • Unsuccessful oral therapy – failure, poor adherence, intolerance
  • Malabsorption (e.g., celiac disease, bariatric surgery)
  • Inflammatory bowel disease
  • Chronic kidney disease receiving erythropoiesis-stimulating drugs
  • Rapid increase in iron required (e.g., pre-operatively for urgent surgery or following acute blood loss)
  • Heart failure.

After oral supplements have been taken for 60–90 days, fasting iron studies are repeated one week after stopping therapy to check if the iron deficiency has been corrected.

If repletion has not occurred, re-investigation is recommended. Iron studies should be repeated approximately 60–90 days, or as clinically appropriate, after intravenous iron therapy.

If there is no response to oral iron therapy or if iron deficiency recurs, further investigations should be considered to exclude blood loss or malabsorption.

A fall in hemoglobin concentration may be significant even if the patient does not become anemic. Depending on the clinical findings, referral to a gynecologist or a gastroenterologist may be appropriate.

Optimal Takeaways

  • Correcting iron deficiency before anemia develops can potentially improve symptoms and enhance quality of life, although the evidence supporting this is mixed.
  • Managing iron deficiency involves identifying and addressing the underlying cause.
  • For straightforward cases, oral iron supplements are typically effective, safe, and cost-effective.
  • However, for patients who cannot tolerate oral iron or where it may be ineffective or harmful, intravenous iron is the recommended alternative.
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Balendran, Shalini, and Cecily Forsyth. “Non-anaemic iron deficiency.” Australian prescriber vol. 44,6 (2021): 193-196. doi:10.18773/austprescr.2021.052 This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND) 4.0 License.


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