Definition/General
Introduction:
Iron deficiency represents the most common nutritional deficiency worldwide, characterized by depletion of body iron stores
Bone marrow iron deficiency shows absent or markedly reduced stainable iron in macrophages
It progresses through stages: iron depletion, iron deficiency without anemia, and iron deficiency anemia
The condition is diagnosed by Prussian blue staining of bone marrow.
Origin:
Results from inadequate iron intake, increased iron requirements, or blood loss
Dietary insufficiency common in vegetarian populations
Menstrual blood loss in women of reproductive age
Gastrointestinal bleeding from various causes
Malabsorption due to celiac disease, gastric surgery
Pregnancy and lactation increase iron requirements.
Classification:
Stage 1: Iron depletion with reduced ferritin, normal hemoglobin
Stage 2: Iron deficiency without anemia, reduced transferrin saturation
Stage 3: Iron deficiency anemia with microcytic, hypochromic RBCs
Absolute iron deficiency: true iron depletion
Functional iron deficiency: adequate stores but impaired utilization.
Epidemiology:
Global prevalence: affects 25% of world population
India: 50-60% women and 25% men affected
Children: 40-50% prevalence in developing countries
Pregnancy: 40-50% prevalence globally
Leading cause of microcytic anemia worldwide
Rural areas show higher prevalence than urban areas.
Clinical Features
Presentation:
Fatigue and weakness (most common)
Pallor of conjunctiva, nail beds, and palms
Shortness of breath on exertion
Palpitations and chest discomfort
Restless leg syndrome
Cold intolerance
Decreased exercise tolerance.
Symptoms:
Easy fatigability and lethargy
Pica (craving for ice, starch, dirt)
Koilonychia (spoon-shaped nails)
Angular cheilitis and glossitis
Hair loss and brittle nails
Headache and dizziness
Cognitive impairment in severe cases.
Risk Factors:
Female sex (menstruation, pregnancy)
Vegetarian diet without adequate iron sources
Infancy and adolescence (rapid growth)
Gastrointestinal disorders (peptic ulcer, inflammatory bowel disease)
Blood donation (frequent donors)
Malabsorption syndromes
Low socioeconomic status.
Screening:
Complete blood count showing microcytic, hypochromic anemia
Serum ferritin (<15 ng/mL suggests deficiency)
Transferrin saturation (<16% suggests deficiency)
Serum iron and total iron-binding capacity
Soluble transferrin receptor (elevated in deficiency)
Bone marrow iron stain (gold standard).
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Gross Description
Appearance:
Bone marrow aspirate appears normocellular to hypercellular
Erythroid hyperplasia with increased M:E ratio
Absence of visible iron particles in unstained smears
Normal megakaryocyte count and morphology.
Characteristics:
Microcytic, hypochromic red blood cells
Increased polychromasia reflecting reticulocytosis
Target cells and elliptocytes may be present
Thrombocytosis (reactive) in 50% of cases.
Size Location:
Uniform distribution of cellular elements
Normal bone marrow architecture preserved
Increased erythroblast concentration in active hematopoietic areas
Normal fat-to-cell ratio in most cases.
Multifocality:
Systemic iron depletion affects all hematopoietic sites
Spleen shows reduced iron stores
Liver demonstrates decreased iron content
Heart may show iron deficiency cardiomyopathy in severe cases.
Microscopic Description
Histological Features:
Erythroid hyperplasia with increased erythroblasts
Micronormoblasts with decreased cytoplasm
Nuclear-cytoplasmic asynchrony in erythroblasts
Ragged cytoplasmic borders in developing RBCs
Absent hemosiderin in bone marrow macrophages.
Cellular Characteristics:
Erythroblasts show decreased hemoglobinization
Pale, scanty cytoplasm in orthochromatic normoblasts
Delayed nuclear maturation relative to cytoplasm
Increased mitotic activity in erythroid precursors
Normal megakaryocyte morphology.
Architectural Patterns:
Preserved bone marrow architecture
Erythroid islands show increased cellularity
Normal distribution of hematopoietic elements
Absence of dysplastic changes
Normal reticulin fiber pattern.
Grading Criteria:
Iron stores grading: Grade 0 (absent), Grade 1+ (decreased), Grade 2+ (normal), Grade 3+ (increased)
Iron deficiency: Grade 0 iron stores
Sideroblast count: <15% (normal >20%)
Erythroid hyperplasia: mild to moderate increase.
Immunohistochemistry
Positive Markers:
Prussian blue stain (iron stain): negative for hemosiderin in macrophages
Glycophorin A: positive in erythroid precursors
CD71 (transferrin receptor): increased expression in erythroblasts
Perls stain: absence of blue granules in macrophages.
Negative Markers:
Hemosiderin: absent in bone marrow macrophages
Ferritin staining: reduced or absent in storage cells
Iron-positive granules: absent in sideroblasts
Storage iron: depleted in reticuloendothelial cells.
Diagnostic Utility:
Prussian blue stain: gold standard for assessing iron stores
Sideroblast enumeration: reduced percentage in iron deficiency
Quantitative iron assessment: grades 0-4+ system
Correlation with serum markers: ferritin, transferrin saturation
Monitoring treatment response: iron repletion over time.
Molecular Subtypes:
True iron deficiency: absent bone marrow iron stores
Functional iron deficiency: present stores but impaired mobilization
Iron-restricted erythropoiesis: chronic inflammation with iron sequestration
Combined deficiency: iron deficiency with B12/folate deficiency.
Molecular/Genetic
Genetic Mutations:
Hereditary iron deficiency: rare genetic forms with TMPRSS6 mutations
Iron-refractory iron deficiency anemia (IRIDA): TMPRSS6 gene mutations
Transferrin deficiency: congenital atransferrinemia
DMT1 mutations: impaired iron transport
Ceruloplasmin deficiency: affects iron utilization.
Molecular Markers:
Hepcidin levels: appropriately suppressed in iron deficiency
Transferrin receptor: upregulated in iron-deficient cells
Ferritin synthesis: decreased due to iron regulatory proteins
Iron regulatory proteins (IRP1/IRP2): activated in iron deficiency
Hypoxia-inducible factors: upregulated to enhance iron absorption.
Prognostic Significance:
Excellent prognosis with appropriate iron replacement
Rapid response to oral iron therapy in most cases
Reticulocyte response: begins within 3-5 days of treatment
Hemoglobin normalization: 6-8 weeks with adequate treatment
Iron store repletion: requires 3-6 months after hemoglobin normalization.
Therapeutic Targets:
Oral iron supplementation: ferrous sulfate, ferrous gluconate
Intravenous iron: for malabsorption or intolerance
Dietary counseling: iron-rich foods, vitamin C enhancement
Treatment of underlying cause: GI bleeding, menorrhagia
Monitoring parameters: hemoglobin, ferritin, transferrin saturation.
Differential Diagnosis
Similar Entities:
Anemia of chronic disease (normal/increased iron stores)
Thalassemia trait (normal iron stores, elevated HbA2)
Sideroblastic anemia (increased iron stores, ring sideroblasts)
Lead poisoning (basophilic stippling, normal iron stores)
Chronic kidney disease (functional iron deficiency).
Distinguishing Features:
Iron deficiency: absent bone marrow iron, low ferritin, high TIBC
Chronic disease: normal/increased iron stores, low transferrin
Thalassemia: normal iron stores, elevated HbA2, family history
Sideroblastic anemia: ring sideroblasts, increased iron stores
Lead poisoning: basophilic stippling, elevated blood lead.
Diagnostic Challenges:
Combined iron and chronic disease: requires soluble transferrin receptor
Early iron deficiency: normal hemoglobin with depleted stores
Functional iron deficiency: adequate stores but impaired utilization
Chronic GI bleeding: ongoing losses vs
repletion
Pregnancy: hemodilution vs
true deficiency.
Rare Variants:
Iron-refractory iron deficiency anemia (IRIDA): genetic hepcidin deficiency
Pulmonary hemosiderosis: iron deficiency with lung bleeding
Intravascular hemolysis: iron loss via hemoglobinuria
Hereditary hemorrhagic telangiectasia: chronic GI bleeding
Celiac disease: malabsorption-related deficiency.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Cellularity
Bone marrow cellularity: [percentage]% with M:E ratio of [ratio]
Iron Stain (Prussian Blue)
Iron stores: Grade [0-4+], Sideroblasts: [percentage]% (normal >20%)
Erythroid Morphology
Erythroid hyperplasia with micronormoblasts showing [hemoglobinization pattern]
Megakaryocytes
Megakaryocytes: [number] and morphology [normal/abnormal]
Other Findings
Myeloid series: [normal/abnormal], Lymphocytes: [percentage]%
Final Diagnosis
Bone marrow consistent with iron deficiency (absent iron stores, Grade 0)
Recommendations
Correlate with serum ferritin and transferrin saturation. Investigate underlying cause of iron deficiency