Early Signs of Iron Deficiency
The earliest clinical signs of iron deficiency are often nonspecific symptoms including fatigue, irritability, difficulty concentrating, and exercise intolerance, which can occur before anemia develops. 1
Clinical Manifestations by Stage
Stage 1: Depleted Iron Stores (Non-Anemic Iron Deficiency)
Iron deficiency progresses through stages, with symptoms appearing even before anemia develops. 1
Common early symptoms include:
- Fatigue and lethargy - among the most frequent presenting complaints 1, 2
- Irritability and mood changes - including depression 1, 3
- Difficulty concentrating and impaired attention - affecting cognitive performance 3, 4
- Exercise intolerance and reduced physical capacity 1, 2
- Restless legs syndrome - present in 32-40% of iron deficient patients 1
- Pica (craving non-food items) - occurs in 40-50% of cases 1
Stage 2: Iron-Deficient Erythropoiesis
As deficiency progresses, additional signs emerge:
- Pallor - the most frequent physical finding on examination 2
- Poor appetite 2
- Dizziness and lightheadedness 1, 2
Stage 3: Iron Deficiency Anemia
More severe manifestations appear with established anemia:
- Dyspnea (shortness of breath) 1, 2
- Tachycardia 2
- Diaphoresis and poor capillary refilling (in severe cases) 2
- Worsening heart failure in patients with pre-existing cardiac disease 1
Special Population Considerations
Children and Infants
Developmental and behavioral changes are particularly important early indicators: 3
- Decreased motor activity 3
- Reduced social interaction 3
- Impaired attention to tasks 3
- Developmental delays - these may persist even after iron repletion if deficiency occurs early in life 3, 2
Pregnant Women
Iron deficiency affects up to 84% of pregnant women by the third trimester in high-income countries, making early detection critical. 1
Laboratory Detection of Early Iron Deficiency
Serum ferritin is the earliest and most specific laboratory indicator of depleted iron stores: 5
- Ferritin <30 ng/mL indicates iron deficiency in individuals without inflammatory conditions 1
- Ferritin ≤15 ng/mL confirms iron deficiency in women with anemia (75% sensitivity, 98% specificity) 5
- Ferritin <12 ng/mL in the general population indicates absolute iron deficiency 5
Important caveat: Ferritin is an acute-phase reactant and can be falsely elevated by infection, inflammation, liver disease, or malignancy, potentially masking depleted iron stores. 5
Transferrin saturation <20% also indicates iron deficiency and is particularly useful when inflammatory conditions are present. 1
Elevated erythrocyte protoporphyrin (>30 μg/dL in adults, >80 μg/dL in children aged 1-2 years) indicates iron-deficient erythropoiesis earlier than anemia appears, though it is less specific than ferritin. 5
Key Clinical Pitfalls
Many patients with early iron deficiency are asymptomatic, making laboratory screening essential in high-risk populations. 1, 2
Symptoms are often nonspecific and may be attributed to other conditions, leading to delayed diagnosis. The presence of fatigue, restless legs syndrome, or pica should prompt iron studies. 1
Normal hemoglobin does not exclude iron deficiency - approximately 38% of nonpregnant reproductive-age women have iron deficiency without anemia. 1
Microcytosis and hypochromia appear later in the disease course, so their absence does not rule out early iron deficiency. 5, 2
High-Risk Groups Requiring Vigilance
Testing should be considered in patients with: 1
- Heavy menstrual bleeding (affects 38% of reproductive-age women)
- Pregnancy (especially second and third trimesters)
- Inflammatory bowel disease (13-90% prevalence)
- Chronic kidney disease (24-85% prevalence)
- Heart failure (37-61% prevalence)
- Cancer (18-82% prevalence)
- History of bariatric surgery or malabsorptive conditions
- Chronic NSAID use