Low Iron Without Anemia and Its Relationship to Fatigue
Iron deficiency without anemia can cause significant fatigue and should be considered as a treatable cause in patients presenting with fatigue symptoms, even when hemoglobin levels are normal. 1
Diagnostic Considerations
Defining Iron Deficiency Without Anemia
- Iron deficiency without anemia (non-anemic iron deficiency) is defined as low iron stores without reduced hemoglobin levels
- Diagnostic parameters include:
- Low ferritin (<30 μg/L in patients without inflammation)
- Low transferrin saturation (<20%)
- Normal hemoglobin levels 2
- In patients with inflammatory conditions, ferritin threshold for iron deficiency may be higher (<100 μg/L) 2
Prevalence and Risk Factors
- Affects approximately 38% of non-pregnant women of reproductive age in high-income countries 1
- Common risk factors include:
- Menstrual bleeding
- Gastrointestinal blood loss
- Impaired iron absorption (atrophic gastritis, celiac disease, bariatric surgery)
- Inadequate dietary iron intake
- Pregnancy
- Inflammatory conditions (IBD, chronic kidney disease, heart failure) 1
Evidence on Iron Deficiency and Fatigue
Relationship Between Non-Anemic Iron Deficiency and Fatigue
- A 2018 systematic review and meta-analysis of randomized controlled trials found that iron supplementation was associated with reduced self-reported fatigue in iron-deficient non-anemic adults (standardized mean difference -0.38; 95% CI -0.52 to -0.23) 3
- However, the same review found no significant differences in objective measures of physical capacity 3
Clinical Manifestations
- Individuals with non-anemic iron deficiency may experience:
- Fatigue
- Irritability
- Depression
- Difficulty concentrating
- Restless legs syndrome (32-40%)
- Exercise intolerance 1
Treatment Approaches
Oral Iron Supplementation
- First-line therapy for most patients with non-anemic iron deficiency 1
- Standard approach: 50-100 mg elemental iron daily 2
- Alternative dosing:
- Common side effects include:
- Constipation (12% of patients)
- Diarrhea (8% of patients)
- Nausea (11% of patients) 2
Intravenous Iron Therapy
- A 2020 prospective study showed significant improvement in fatigue scores at 4 weeks and 12 weeks after IV iron therapy in non-anemic iron-deficient patients 4
- Indications for IV iron over oral iron include:
- IV iron formulations can deliver complete iron repletion in just two administrations 2
Monitoring and Follow-up
- Complete follow-up iron studies should be done after 8-10 weeks of treatment 2
- Patients should be reassessed after 2-4 weeks of oral therapy to evaluate response 2
- After successful treatment, monitoring for recurrent iron deficiency should be done every 3 months for at least a year 2
Important Clinical Considerations
Pitfalls to Avoid
- Failing to test for iron deficiency in patients with fatigue but normal hemoglobin levels
- Checking ferritin levels too early after IV iron administration (will be falsely elevated) 2
- Overlooking iron deficiency in patients with inflammatory conditions (using inappropriate ferritin cutoffs) 2
- Not investigating the underlying cause of iron deficiency 1
Special Populations
- Patients with inflammatory bowel disease may have poor absorption of oral iron and experience more side effects 5, 2
- A cross-sectional study of IBD outpatients found that 19% had anemia and 35% had iron deficiency, though interestingly, fatigue (present in 44%) was not associated with anemia or iron deficiency in this specific population 6
In conclusion, the evidence supports a significant relationship between non-anemic iron deficiency and fatigue, with multiple studies showing improvement in fatigue symptoms following iron supplementation, particularly intravenous iron therapy for those who don't respond to or tolerate oral supplementation.