Early Signs of Iron Deficiency
Iron deficiency progresses through distinct stages, with the earliest signs being completely asymptomatic depletion of iron stores, followed by functional iron deficiency, and finally iron-deficiency anemia with its characteristic symptoms. 1
Stages of Iron Deficiency Progression
Iron deficiency represents a spectrum that evolves through three distinct phases 1:
Stage 1: Iron Depletion (Earliest Stage)
- Reduced stored iron (measured by low serum ferritin) but no physiological impairments 1
- Patients are completely asymptomatic at this stage 1
- No iron stores available to mobilize if the body requires more iron 1
- This is the earliest detectable stage but requires biochemical testing, as there are no clinical signs 1
Stage 2: Iron-Deficient Erythropoiesis
- Stored iron is depleted and transport iron (transferrin saturation) becomes reduced 1
- Iron shortage begins to limit red blood cell production 1
- Increased erythrocyte protoporphyrin concentration develops 1
- Patients may begin experiencing subtle symptoms but often remain undiagnosed 1
Stage 3: Iron-Deficiency Anemia (Late Stage)
- This is when most clinical signs become apparent 1
- Red blood cells become microcytic and hypochromic 1
Clinical Manifestations When Symptoms Develop
General Symptoms (Most Common)
- Fatigue (most frequently reported symptom) 2, 3
- Irritability and difficulty concentrating 2
- Depression 2
- Exercise intolerance and dyspnea 2
- Lightheadedness 2
Specific Early Signs
- Restless legs syndrome (affects 32%-40% of iron-deficient patients) 2, 3
- Pica, particularly ice craving (pagophagia) (affects 40%-50% of patients) 2, 4, 3
- Poor work function and decreased intellectual performance 3
- Increased susceptibility to infection 3
Age-Specific Manifestations
In infants and preschool children (ages 0-5 years):
- Developmental delays 1
- Behavioral disturbances including decreased motor activity 1
- Decreased social interaction 1
- Reduced attention to tasks 1
- These developmental delays may persist past school age if iron deficiency is not fully reversed 1
- Increased gastrointestinal absorption of lead, contributing to lead poisoning 1
In adults:
In pregnant women:
- Worsening quality of life 4
- Gastrointestinal symptoms if taking oral iron supplementation 4
- Iron-deficiency anemia during the first two trimesters is associated with twofold increased risk for preterm delivery and threefold increased risk for low-birthweight babies 1
Critical Diagnostic Considerations
The key clinical pitfall is that early iron deficiency (Stage 1: iron depletion) produces no symptoms or signs 1. Detection requires:
- Biochemical testing with serum ferritin (typically <30 ng/mL without inflammation or <45 ng/mL as recommended by AGA) 1, 2
- Transferrin saturation <20% 2
- Hemoglobin concentration and hematocrit are late indicators and only become abnormal in iron-deficiency anemia, not early iron deficiency 1
Important Caveats
- Ferritin is an acute-phase reactant and can be falsely elevated during illness, inflammation, or stress 5, making diagnosis challenging in patients with chronic inflammatory conditions 2
- In inflammatory conditions, transferrin saturation <20% (performed after overnight fast) should be used instead 3
- Symptoms are often nonspecific and may be attributed to other causes, leading to underdiagnosis and undertreatment 4
Population-Specific Risk Factors to Identify
Premenopausal women:
- Heavy menstrual bleeding 1, 2, 3
- Pregnancy (affects up to 84% in third trimester) 2, 4
- Poor dietary intake 1
Men and postmenopausal women:
- Gastrointestinal blood loss (peptic ulcer, inflammatory bowel disease, bowel cancer) 1
- Use of NSAIDs or aspirin 1, 2
All patients: