• Classify anemia. Describe iron deficiency anemia — causes, pathogenesis, clinical features, lab findings and peripheral smear from Robbins Tripura based exam format

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Iron Deficiency Anemia

Based on Robbins, Cotran & Kumar - Pathologic Basis of Disease

A. CLASSIFICATION OF ANEMIA

Anemia is defined as a reduction of the total circulating red cell mass below normal limits, reducing the oxygen-carrying capacity of the blood and leading to tissue hypoxia. There are two major classification systems:

I. By Underlying Mechanism (Table 14.1, Robbins)

Mechanism	Examples
Blood Loss	Acute (trauma); Chronic (GI lesions, gynecologic)
Increased RBC Destruction (Hemolysis)
- Inherited	Hereditary spherocytosis, G6PD deficiency, pyruvate kinase deficiency, thalassemias, sickle cell disease
- Acquired	PNH, autoimmune hemolytic anemia, microangiopathic (HUS, DIC, TTP), malaria
Decreased RBC Production
- Nutritional	Iron deficiency (↓ Hb synthesis); B12/folate deficiency (↓ DNA synthesis)
- Stem cell failure	Aplastic anemia, Fanconi anemia
- Erythropoietin deficiency	Renal failure
- Bone marrow replacement	Leukemia, myelophthisis
- Inflammation-mediated	Anemia of chronic disease

II. By Morphology (Clinically Useful Approach)

Type	MCV	Causes
Microcytic hypochromic	<80 fL	Iron deficiency, thalassemia, sideroblastic anemia, anemia of chronic disease
Normocytic normochromic	80-100 fL	Acute blood loss, hemolytic anemia, aplastic anemia, renal disease
Macrocytic	>100 fL	B12/folate deficiency (megaloblastic), liver disease, hypothyroidism

B. IRON DEFICIENCY ANEMIA

Iron deficiency is the most common nutritional disorder in the world and the most frequent cause of anemia. It is especially prevalent in toddlers, adolescent girls, and females of childbearing age.

1. IRON METABOLISM (Background)

Iron metabolism cycle showing flow from intestinal absorption through plasma transferrin to bone marrow erythroid precursors, circulating red cells, mononuclear phagocyte stores, liver, and back

Fig. 14.20 - Iron metabolism cycle (Robbins)

Key facts:

Normal daily diet contains 10-20 mg iron; only 1-2 mg absorbed (heme iron 20% absorbed vs. nonheme iron 1-2% absorbed)
Daily losses: 1-2 mg/day in shed epithelial cells (skin, gut, endometrium)
Storage forms: Ferritin (hepatocytes, splenic and marrow macrophages) and hemosiderin
Transport: Transferrin - normally ~1/3 saturated; serum iron ~120 µg/dL (males), ~100 µg/dL (females)
Regulation: Hepcidin (liver peptide) - inhibits ferroportin, blocks iron release from macrophages and gut enterocytes

2. CAUSES (Etiology)

Iron deficiency results from four mechanisms:

Cause	Details
1. Dietary lack	Low-resource countries (inadequate diet, plant-based inorganic iron); infants (breast milk only 0.3 mg/L), vegans, elderly, impoverished
2. Impaired absorption	Sprue/celiac disease, gastrectomy (↓ acidity in duodenum, rapid transit), chronic diarrhea; inhibited by tannins (tea), carbonates, oxalates, phosphates
3. Increased requirement	Growing infants, children, adolescents; premenopausal females; pregnancy (especially multiple pregnancies in low-resource settings)
4. Chronic blood loss (Most common in developed countries)	GI bleeding (peptic ulcer, GI cancer, hookworm), gynecologic (menorrhagia); iron deficiency in adult males and postmenopausal females must be attributed to GI blood loss until proven otherwise

Key exam point: In adult males and postmenopausal females in high-income countries, always suspect GI malignancy as the source. "An alert clinician investigating unexplained iron deficiency anemia occasionally discovers an occult bleeding source such as cancer and thereby saves a life." - Robbins

3. PATHOGENESIS

The sequence of iron depletion is three-stage and progressive:

Stage 1 - Pre-latent (Depletion of iron stores):

Storage iron (ferritin/hemosiderin) is consumed
Serum ferritin falls (first marker to drop)
Hemoglobin, hematocrit, and serum iron are still normal
No anemia yet; bone marrow shows increased erythroid activity

Stage 2 - Latent (Iron-deficient erythropoiesis):

Iron stores completely depleted
Serum iron falls, TIBC (transferrin) rises
Transferrin saturation falls below 15%
Erythroid precursors are iron-starved but anemia is mild/absent
Hepcidin synthesis is inhibited (serum hepcidin falls)

Stage 3 - Frank Iron Deficiency Anemia:

Insufficient iron for hemoglobin synthesis
Hypochromic microcytic anemia develops
All iron indices are abnormal
Systemic enzyme depletion causes extra-hematologic features

Molecular mechanism:

Without iron, heme synthesis fails → inadequate hemoglobin → smaller, paler RBCs
Iron-containing enzymes (catalase, cytochromes) depleted throughout body → tissue effects
Reduced hepcidin synthesis → attempted compensation by upregulating duodenal iron absorption

4. CLINICAL FEATURES

A. General Features of Anemia (from tissue hypoxia):

Pallor, fatigue, weakness, exertional dyspnea
Palpitations, tachycardia
Headache, dizziness, irritability
In severe cases: high-output cardiac failure

B. Features Specific to Iron Deficiency (from iron-containing enzyme depletion):

Feature	Description
Koilonychia	Spoon-shaped nails (loss of nail plate convexity)
Alopecia	Hair loss
Atrophic glossitis	Smooth, beefy-red tongue (loss of papillae)
Angular stomatitis	Fissuring at corners of mouth
Pica	Craving for non-food substances (clay, ice = pagophagia, flour) - from CNS iron depletion
Plummer-Vinson syndrome	Triad: microcytic hypochromic anemia + atrophic glossitis + esophageal webs (rare)
Gastric atrophy	Achlorhydria

C. Signs related to underlying cause:

Symptoms of GI bleeding (melena, hematochezia)
Menorrhagia in females

5. LABORATORY FINDINGS

Parameter	Finding in IDA
Hemoglobin / Hematocrit	Decreased (moderate degree)
MCV (Mean Cell Volume)	Decreased (<80 fL) - microcytic
MCH	Decreased - hypochromic
MCHC	Decreased
RDW	Increased (anisocytosis - variable cell size)
Serum iron	Low
TIBC (Total Iron Binding Capacity)	High (reflects elevated transferrin)
Transferrin saturation	<15% (normally 25-50%)
Serum ferritin	Low (<12 µg/L) - most sensitive early indicator
Serum hepcidin	Low (reduced iron stores inhibit hepcidin synthesis)
Reticulocyte count	Low or normal (hypoproliferative)
Bone marrow iron (Prussian blue)	Absent stainable iron in macrophages - diagnostically significant

Response to treatment:

Oral iron supplementation → reticulocytosis in 5-7 days → gradual rise in Hb → normalization of RBC indices

6. PERIPHERAL BLOOD SMEAR

Iron deficiency anemia peripheral blood smear showing hypochromic microcytic red cells with narrow rim of peripheral hemoglobin and pencil cells

Fig. 14.22 - Iron deficiency anemia peripheral blood smear (Robbins). Note hypochromic microcytic RBCs with narrow rim of peripheral hemoglobin. The scattered fully hemoglobinized cells are present due to recent blood transfusion.

Findings on peripheral smear:

Finding	Description
Microcytosis	Small red cells (MCV <80 fL)
Hypochromia	Enlarged zone of central pallor; hemoglobin seen only as a narrow peripheral rim (normal central pallor = 1/3 of cell diameter)
Poikilocytosis	Abnormal cell shapes
"Pencil" cells (Elliptocytes)	Small, elongated red cells - characteristically seen
Anisocytosis	Variation in cell size (elevated RDW)

If the patient has recently received a blood transfusion, scattered fully hemoglobinized normochromic cells stand in contrast to the patient's hypochromic cells - an important diagnostic clue (as seen in Fig. 14.22).

Quick Summary Table (Exam Recall)

Feature	IDA
Type	Microcytic hypochromic
Most common cause (developed)	Chronic GI blood loss
Most common cause (global)	Dietary deficiency / hookworm
Serum iron	↓
TIBC	↑
Ferritin	↓↓ (most sensitive marker)
Hepcidin	↓
Smear	Microcytic, hypochromic, pencil cells, anisocytosis
Bone marrow	No stainable iron (Prussian blue negative)
Nails	Koilonychia
Pica	Classic feature

Source: Robbins, Cotran & Kumar - Pathologic Basis of Disease (10th ed.), Chapter 14, pp. 612-615

Exam pattern

Here is the same content reformatted in the standard Tripura/university exam answer pattern:

ANEMIA — CLASSIFICATION AND IRON DEFICIENCY ANEMIA

DEFINITION

Anemia is defined as a reduction of the total circulating red cell mass below normal limits, leading to decreased oxygen-carrying capacity of the blood and resultant tissue hypoxia.

CLASSIFICATION OF ANEMIA

A. Based on Underlying Mechanism (Robbins)

I. Blood Loss

Acute — Trauma
Chronic — GI tract lesions, gynecologic disturbances

II. Increased Red Cell Destruction (Hemolytic Anemia)

(a) Inherited:

RBC membrane defects — Hereditary spherocytosis, elliptocytosis
Enzyme deficiencies — G6PD deficiency, Pyruvate kinase deficiency
Hemoglobin defects — Thalassemia syndromes, Sickle cell disease

(b) Acquired:

PNH (Paroxysmal nocturnal hemoglobinuria)
Immune-mediated — Autoimmune hemolytic anemia, transfusion reactions, HDN
Microangiopathic — HUS, DIC, TTP
Infections — Malaria, babesiosis

III. Decreased Red Cell Production

Nutritional deficiencies — Iron deficiency, B12/Folate deficiency
Stem cell failure — Aplastic anemia
EPO deficiency — Chronic renal failure
Marrow replacement — Leukemia, myelophthisis
Inflammation-mediated — Anemia of chronic disease

B. Based on Morphology (MCV)

Type	MCV	Examples
Microcytic hypochromic	<80 fL	Iron deficiency, Thalassemia, Sideroblastic anemia
Normocytic normochromic	80–100 fL	Aplastic anemia, Hemolytic anemia, Acute blood loss
Macrocytic	>100 fL	B12/Folate deficiency, Liver disease

IRON DEFICIENCY ANEMIA (IDA)

Definition: Most common nutritional disorder in the world; results from inadequate iron for hemoglobin synthesis, producing a hypochromic microcytic anemia.

CAUSES (Etiology)

Iron deficiency arises from four mechanisms:

1. Dietary Lack

Most common globally; low-resource countries with plant-based (nonheme) diets
At-risk groups in developed countries: infants (breast milk only 0.3 mg/L iron), vegans, elderly, impoverished

2. Impaired Absorption

Sprue/celiac disease, chronic diarrhea
Gastrectomy — reduces gastric acidity and increases duodenal transit time
Dietary inhibitors — tannins (tea), carbonates, oxalates, phosphates

3. Increased Requirement

Growing children and adolescents
Pregnancy and lactation
Premenopausal females

4. Chronic Blood Loss (Most common cause in developed countries)

GI bleeding — peptic ulcer, colorectal carcinoma, hookworm infestation
Gynecologic — menorrhagia
Important: Iron deficiency in adult males and postmenopausal females must be attributed to GI blood loss (occult malignancy) until proven otherwise

PATHOGENESIS

Iron deficiency develops in three sequential stages:

Stage 1 — Pre-latent (Storage depletion)

Ferritin/hemosiderin stores consumed
Serum ferritin falls (first marker to drop)
Serum iron, TIBC, Hb — still normal
Compensatory increase in bone marrow erythroid activity

Stage 2 — Latent (Iron-deficient erythropoiesis)

Iron stores completely exhausted
Serum iron falls; TIBC rises (elevated transferrin)
Transferrin saturation falls below 15%
Hepcidin synthesis falls (low iron stores suppress hepcidin)
Mild or no anemia

Stage 3 — Frank IDA

Hemoglobin synthesis fails due to lack of iron
Hypochromic microcytic anemia develops
Iron-containing enzymes depleted throughout body → extra-hematologic features

Key molecular steps:

Fe²⁺ absorbed in proximal duodenum via DMT1 (nonheme) and transporters (heme)
Exported across enterocyte basolateral membrane by ferroportin
Hepcidin (liver) normally inhibits ferroportin → in IDA, hepcidin falls → maximizes absorption
Iron transported in plasma bound to transferrin → delivered to erythroid precursors via receptor-mediated endocytosis

CLINICAL FEATURES

A. General Features of Anemia (tissue hypoxia):

Pallor, fatigue, weakness
Exertional dyspnea, palpitations, tachycardia
Headache, dizziness, poor concentration
High-output cardiac failure in severe/chronic cases

B. Features Specific to Iron Deficiency (from depletion of iron-containing enzymes):

Feature	Description
Koilonychia	Spoon-shaped (concave) nails
Alopecia	Hair loss
Atrophic glossitis	Smooth, bald tongue (loss of papillae)
Angular stomatitis	Fissuring at corners of mouth
Pica	Craving for non-food items (clay, ice = pagophagia)
Plummer-Vinson syndrome	Triad: microcytic hypochromic anemia + atrophic glossitis + esophageal webs
Gastric atrophy	Achlorhydria, intestinal malabsorption

LABORATORY FINDINGS

Investigation	Finding
Hemoglobin / Hematocrit	↓ (moderate)
MCV	↓ (<80 fL) — microcytic
MCH / MCHC	↓ — hypochromic
RDW	↑ (increased anisocytosis)
Serum iron	↓↓
TIBC	↑↑ (elevated transferrin)
Transferrin saturation	<15% (normal 25–50%)
Serum ferritin	↓↓ (<12 µg/L) — most sensitive early marker
Serum hepcidin	↓
Reticulocyte count	Low/normal
Bone marrow (Prussian blue stain)	Absent stainable iron in macrophages — diagnostically significant

Response to oral iron therapy:

Reticulocytosis appears in 5–7 days
Steady rise in Hb and normalization of RBC indices follows

PERIPHERAL BLOOD SMEAR

Fig. 14.22, Robbins — IDA peripheral smear. Hypochromic microcytic RBCs with narrow peripheral rim of hemoglobin. Scattered normochromic cells due to recent transfusion.

Findings:

Feature	Description
Microcytosis	Small RBCs (MCV <80 fL)
Hypochromia	Enlarged central pallor; hemoglobin confined to narrow peripheral rim (normal pallor = 1/3 cell diameter)
Pencil cells	Small elongated (elliptoid) RBCs — characteristic of IDA
Anisocytosis	Variation in cell size
Poikilocytosis	Variation in cell shape
Target cells	May be seen in severe cases

SUMMARY BOX (Rapid Recall)

Point	IDA
Type	Microcytic hypochromic
Most common cause globally	Dietary/hookworm
Most common cause (developed)	Chronic GI blood loss
Serum iron	↓
TIBC	↑
Ferritin	↓ (earliest marker)
Hepcidin	↓
Smear	Microcytic, hypochromic, pencil cells
Bone marrow	Prussian blue negative
Nail finding	Koilonychia
Pica	Pagophagia (ice craving)
Syndrome	Plummer-Vinson
Rx response	Reticulocytosis in 5–7 days

Source: Robbins, Cotran & Kumar - Pathologic Basis of Disease, Chapter 14, pp. 594–615

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