What is iron deficiency anemia, its pathogenesis, epidemiology, clinical manifestations, expected physical examination findings, and laboratory results?

Iron Deficiency Anemia: Comprehensive Overview

Definition

Iron deficiency anemia (IDA) is defined as hemoglobin concentration below the lower limit of normal for the relevant population, confirmed by iron studies showing depleted iron stores, most reliably indicated by low serum ferritin. 1

• Anemia is diagnosed when hemoglobin falls below population-specific thresholds (typically <13 g/dL in men, <12 g/dL in non-pregnant women) 1
• Iron deficiency without inflammation is confirmed by serum ferritin <30 μg/L with 93% specificity in women of childbearing age and 92% in children aged 1-5 years 2
• Serum ferritin <12 μg/L is diagnostic of iron deficiency regardless of inflammatory status 2
• In the presence of inflammation (elevated CRP/ESR), ferritin up to 100 μg/L may still indicate iron deficiency since ferritin acts as an acute phase reactant 1, 2

Pathogenesis

Iron deficiency develops through three progressive stages: depletion of iron stores, iron-deficient erythropoiesis, and finally iron deficiency anemia when hemoglobin synthesis becomes impaired. 3

Mechanisms of Iron Deficiency:

• Inadequate intake: Dietary insufficiency, particularly in populations with limited access to iron-rich foods 4, 3
• Impaired absorption: Celiac disease (found in 3-5% of IDA cases), atrophic gastritis, post-bariatric surgery, inflammatory bowel disease affecting duodenal/jejunal mucosa 1, 5
• Increased blood loss: Gastrointestinal bleeding from ulcers, tumors, or inflammatory lesions (62% of adult IDA cases show GI bleeding evidence); menstrual blood loss in women 1, 6
• Increased physiological demands: Pregnancy, lactation, rapid growth periods in children 4, 3
• Inflammation-mediated functional deficiency: Cytokine-driven hepcidin upregulation blocks ferroportin, trapping iron in macrophages and reducing transferrin saturation despite adequate total body iron 1

Epidemiology

Global Burden:

Iron deficiency anemia is a major cause of morbidity worldwide, affecting roughly one-third of the global population, with half of all anemia cases attributable to iron deficiency. 1, 3

• Children aged 0-5 years: 20.1% prevalence in industrialized countries, 39% in developing countries 4
• Children aged 5-14 years: 5.9% in industrialized countries, 48.1% in developing countries 4
• Women of childbearing age: Disproportionately affected due to menstrual blood loss and pregnancy demands 4, 6, 3
• Pregnant women: Particularly high-risk group for both maternal and fetal complications 1, 3

United States-Specific Data:

• Men ≥20 years: ≤2% prevalence of IDA 1
• Postmenopausal women ≥50 years: 2% prevalence of IDA 1
• In men and postmenopausal women with IDA, approximately two-thirds of cases are attributable to chronic disease or inflammatory conditions rather than dietary insufficiency 1

High-Risk Populations:

• Women of reproductive age (menstruation, pregnancy) 4, 6, 3
• Developing fetuses and young children 4, 3
• Patients with chronic inflammatory diseases (IBD, chronic kidney disease, heart failure, cancer) 1, 3
• Elderly populations 4
• Patients with gastrointestinal pathology including malignancy 1, 5

Clinical Manifestations

Iron deficiency anemia presents insidiously with symptoms related to reduced oxygen-carrying capacity and tissue iron depletion, though many patients remain asymptomatic until anemia becomes severe. 1, 3

Common Symptoms:

• Fatigue and weakness: Most common presenting complaint 3
• Dyspnea on exertion: Due to reduced oxygen delivery 3
• Dizziness and lightheadedness: Particularly with postural changes 3
• Headache: Related to cerebral hypoxia 3
• Palpitations: Compensatory tachycardia 3
• Cold intolerance: Impaired thermoregulation 3
• Cognitive impairment: Difficulty concentrating, neurodevelopmental deficits in children 7, 3
• Reduced physical performance: Decreased exercise tolerance and work capacity 3

Less Common Manifestations:

• Pica: Craving for non-nutritive substances (ice, dirt, starch) 3
• Restless leg syndrome: Uncomfortable leg sensations relieved by movement 3
• Angular stomatitis: Cracks at corners of mouth 3
• Glossitis: Smooth, painful tongue 3

Expected Physical Examination Findings

Physical examination findings in IDA are often subtle and may be entirely normal in mild cases, but specific signs become apparent with more severe or prolonged deficiency. 1, 3

General Appearance:

• Pallor: Most reliable sign, best assessed in conjunctivae, palmar creases, and nail beds 3
• Tachycardia: Compensatory response to reduced oxygen-carrying capacity 3
• Systolic flow murmur: High-output state in severe anemia 3

Specific Signs:

• Koilonychia (spoon nails): Concave, brittle nails in chronic severe deficiency 3
• Angular cheilitis: Fissuring at mouth corners 3
• Atrophic glossitis: Smooth, beefy-red tongue with loss of papillae 3
• Blue sclerae: Thinning of sclera revealing underlying choroid 3
• Signs of underlying cause: Abdominal masses, rectal bleeding, signs of malabsorption or inflammatory bowel disease 1, 5

Important Caveat:

• Physical examination has limited sensitivity for detecting mild-to-moderate IDA 3
• A detailed history focusing on blood loss sources, dietary intake, malabsorption symptoms, and medication use is more valuable than physical examination alone 1

Expected Laboratory Results

The diagnostic approach to IDA requires a systematic evaluation starting with complete blood count, followed by iron studies, with interpretation adjusted for inflammatory status. 1, 2

Initial Screening Tests:

• Hemoglobin/Hematocrit: Reduced below age- and sex-specific thresholds; these are late indicators appearing only after iron stores are depleted 1, 2
• Mean Corpuscular Volume (MCV): Typically low (<80 fL), indicating microcytic anemia, though may be normal in early deficiency or combined deficiencies 1, 8
• Red Cell Distribution Width (RDW): Elevated (>14-15%), indicating heterogeneous red cell populations; particularly useful when MCV is normal due to coexisting deficiencies 1, 2, 8

Iron Studies (Essential for Confirmation):

• Serum ferritin: Single most useful marker 1
  • <30 μg/L confirms iron deficiency without inflammation (93% specificity) 2
  • <12 μg/L diagnostic regardless of inflammation 2
  • <100 μg/L may indicate deficiency with active inflammation 1, 2
• Transferrin saturation: Typically <20% in iron deficiency; helps distinguish from anemia of chronic disease 1
• Serum iron: Low, but less reliable due to diurnal variation 1
• Total iron-binding capacity (TIBC): Elevated in iron deficiency 1

Red Blood Cell Morphology:

• Microcytosis: Small red cells (low MCV) 1
• Hypochromia: Pale red cells with increased central pallor 4
• Anisocytosis: Variation in red cell size (elevated RDW) 1, 2

Reticulocyte Count:

• Low or inappropriately normal: Indicates inability to respond adequately to anemia due to iron-deficient erythropoiesis 1
• Elevated reticulocytes exclude deficiency states and suggest hemolysis or bleeding with adequate iron stores 1

Diagnostic Algorithm:

1. Confirm anemia exists: Check hemoglobin/hematocrit against age/sex-specific cutoffs 2
2. Assess MCV and reticulocyte count: Microcytic anemia with low/normal reticulocytes suggests iron deficiency or chronic disease 1, 2
3. Check inflammatory markers: CRP and ESR determine which ferritin threshold to apply 1, 2
4. Measure serum ferritin: Use <30 μg/L cutoff without inflammation, <100 μg/L with inflammation 1, 2
5. Add transferrin saturation: Helps distinguish true iron deficiency from functional deficiency in inflammatory states 1

Therapeutic Diagnostic Test:

• Response to iron therapy: Hemoglobin rise ≥10 g/L (≥1.0 g/dL) within 2-3 weeks is highly suggestive of absolute iron deficiency, even with equivocal iron studies 1, 2

Special Considerations:

• Dimorphic anemia: Coexisting iron and B12/folate deficiency may produce normal MCV with elevated RDW; requires checking both iron studies and B12/folate levels 1, 8
• Anemia of chronic disease vs. IDA: Both can coexist in inflammatory conditions; transferrin receptor/ferritin ratio may help distinguish 2
• No single test is definitive: Diagnosis requires integration of multiple parameters in clinical context 1

Advanced/Rarely Needed Tests:

• Bone marrow aspiration: Absent iron stores on Prussian blue staining is definitive but rarely necessary in clinical practice 2
• Soluble transferrin receptor: Elevated in iron deficiency, normal in anemia of chronic disease; useful when ferritin interpretation is unclear 3