Anemia: Definition and Classification

Definition

• Hemoglobin (Hb) concentration - preferred because it is directly measured (not calculated)
• Hematocrit (Hct) - the ratio of packed red cells to total blood volume (calculated by electronic counters as RBC count × MCV)
• Red blood cell count - reported but rarely used alone to define anemia

Classification

I. Morphologic Classification (by Red Cell Size / MCV)

A. Microcytic Anemia (MCV < 80 fL)

B. Normocytic Anemia (MCV 80-100 fL)

C. Macrocytic Anemia (MCV > 100 fL)

• Vitamin B12 deficiency
• Folate deficiency
• Medications (chemotherapy agents, some antiepileptics, methotrexate)
• Myelodysplastic syndrome

• Alcohol use disorder / liver disease
• Hypothyroidism
• Reticulocytosis (young RBCs are larger)
• Dysproteinemia
• Hypoxia, smoking
• Harrison's Principles of Internal Medicine 22E, p. 492; Goldman-Cecil Medicine, Table 144-9

II. Pathophysiologic (Mechanistic) Classification

• High reticulocytes → bone marrow is responding = increased loss or destruction
• Low/inappropriately normal reticulocytes → bone marrow is failing = underproduction

A. Blood Loss

B. Increased Red Cell Destruction (Hemolytic Anemia)

C. Decreased Red Cell Production (Hypoproliferative)

Summary Table

Iron Deficiency Anemia (IDA): A Complete Discussion

Understanding Iron Metabolism First (the "Why" Foundation)

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 612

• Iron is lost at 1-2 mg/day through shed mucosal and skin cells. There is no regulated excretion pathway - so the body tightly controls absorption to compensate.
• The normal diet contains 10-20 mg/day. Only ~20% of heme iron and 1-2% of non-heme iron is absorbed - so the average Western diet (meat-rich) provides just enough.
• Hepcidin (liver-produced) is the master regulator: it degrades ferroportin on intestinal cells, blocking iron export into blood. When iron stores are low, hepcidin falls, ferroportin increases, and more iron is absorbed. When inflammation occurs, hepcidin rises (IL-6 stimulus) - causing functional iron deficiency (the mechanism of anemia of chronic disease).

Etiology (Causes of Iron Deficiency)

1. Dietary Lack

• Rare in meat-eating populations (heme iron is highly bioavailable)
• Common in:
  • Infants (breast milk has only ~0.3 mg/L iron; very low bioavailability in cow's milk)
  • Vegans/vegetarians (non-heme iron in plants is poorly absorbed; inhibited further by tannins in tea, phosphates, oxalates, phytates)
  • Elderly with restricted diets (poor dentition, limited income)
  • Low-resource countries where most dietary iron is non-heme plant iron

Why? Non-heme iron must be in Fe²⁺ (ferrous) form for absorption. Tannins, carbonates, and phytates stabilize Fe³⁺ (ferric), making it non-absorbable. Ascorbic acid does the opposite - it reduces Fe³⁺ to Fe²⁺ and thus enhances absorption.

2. Impaired Absorption

• Celiac disease / tropical sprue - autoimmune damage to duodenal villi where iron is absorbed
• Gastrectomy - reduced acid production (acidity is needed to reduce Fe³⁺ → Fe²⁺ and release iron from food) + rapid gastric emptying bypasses the duodenum
• H. pylori infection - decreases iron absorption + produces microerosions that bleed
• Proton pump inhibitors - reduce gastric acid, impairing non-heme iron reduction
• Dietary inhibitors: tannins (tea), phytates (cereals), phosphates, calcium

3. Increased Requirements

• Infants and young children - rapid growth demands more iron than milk provides
• Adolescents - growth spurts
• Premenopausal women - menstruation (normal loss ~30-40 mL blood/cycle = ~15-20 mg iron)
• Pregnancy - fetal demands and expanded maternal blood volume increase iron needs to ~5-6 mg/day in the 2nd and 3rd trimesters; this exceeds diet alone

4. Chronic Blood Loss (Most Common Cause in Developed Countries)

• GI tract (most common in adult men and postmenopausal women):
  • Peptic ulcer disease
  • Colorectal cancer / polyps
  • Angiodysplasia
  • Hookworm infestation (major cause in tropical regions - each worm causes ~0.03 mL blood loss/day)
  • NSAIDs causing gastric erosions
• Genitourinary tract: menorrhagia, uterine fibroids, endometrial carcinoma
• Pulmonary: pulmonary hemosiderosis (rare)
• Iatrogenic: repeated phlebotomy, hemodialysis

Critical clinical point: Iron deficiency in an adult male or postmenopausal female must be attributed to GI blood loss until proven otherwise - missing this can mean missing colorectal cancer. - Robbins, Cotran & Kumar, p. 614

Stages of Iron Deficiency (the "Why" for Lab Changes)

Clinical Features

A. Symptoms of Anemia (from reduced O₂ delivery)

• Fatigue, weakness, easy fatigability - tissues are hypoxic
• Dyspnea on exertion - compensatory tachypnea
• Palpitations, tachycardia - compensatory increased cardiac output
• Headache, dizziness, poor concentration - cerebral hypoxia
• Pallor - reduced hemoglobin in superficial vessels

B. Signs Specific to Iron Deficiency

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 615

Investigations

1. Complete Blood Count (CBC)

2. Peripheral Blood Smear (PBS)

• Microcytes - small RBCs
• Hypochromia - enlarged central pallor (> 1/3 cell diameter); hemoglobin visible only as a thin rim
• Pencil cells / cigar cells - elongated, small RBCs (characteristic of IDA)
• Anisocytosis - varying cell sizes
• Poikilocytosis - varying shapes

IDA peripheral blood smear: note the pale, small red cells with a broad central pallor. A transfused, fully hemoglobinized cell is seen in contrast. - Robbins, Cotran & Kumar, p. 615

3. Iron Studies

Why TIBC rises in IDA: When iron is low, the liver produces more transferrin to "capture" what little iron is available. More empty transferrin in the blood = higher TIBC. In contrast, ferritin is an acute phase reactant, so it can be falsely normal or elevated in IDA with co-existing infection/inflammation.

Why ferritin is the best screening test: It directly reflects storage iron. A ferritin < 12 µg/L is virtually diagnostic of IDA, and a level < 30 µg/L is highly sensitive even without overt anemia.

4. Bone Marrow Examination (rarely needed)

• Absence of Prussian blue-staining iron in macrophages = diagnostic gold standard for IDA
• Increased erythroid precursors (erythroid hyperplasia)
• Used when diagnosis is uncertain (e.g., co-existing inflammation elevating ferritin)

5. Other Tests (to identify the cause)

• Stool occult blood test - GI bleeding
• Colonoscopy / upper endoscopy - mandatory in all adult males and postmenopausal women with IDA
• Duodenal biopsy - to rule out celiac disease
• H. pylori testing - serology or stool antigen
• Capsule endoscopy - if all endoscopic procedures are unrevealing
• Reticulocyte count - will rise within 5-7 days of iron supplementation (confirming diagnosis)

Management

Step 1: Identify and Treat the Underlying Cause

• This is the most important step. Replacing iron without finding the source of loss is inadequate - especially if bleeding is from a GI cancer.
• Treat celiac disease (gluten-free diet), H. pylori, control menorrhagia, etc.

Step 2: Iron Supplementation

A. Oral Iron (First-line)

• Ferrous sulfate 325 mg (contains 65 mg elemental iron) once daily on an empty stomach
• Alternatively: ferrous fumarate, ferrous gluconate
• Why empty stomach? Gastric acid enhances Fe³⁺ → Fe²⁺ reduction and absorption. Food, antacids, calcium, and PPIs all reduce absorption.
• Why ferrous (Fe²⁺) not ferric (Fe³⁺)? Only Fe²⁺ is transported by DMT1; Fe³⁺ must first be reduced - so ferrous salts have higher bioavailability.
• Avoid timed-release preparations - iron is released beyond the duodenum where absorption is minimal.
• Vitamin C (ascorbic acid) co-administration enhances absorption by keeping iron in the reduced Fe²⁺ state.

• Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 928

• 5-7 days: reticulocytosis peaks (marrow responds)
• 2-4 weeks: Hb begins to rise significantly
• 1-2 months: Hb normalizes
• 3-6 months: continue iron to replenish stores after Hb is normal (stores replenish slowly at ~100 mg/month)

• Constipation, dark stools
• Nausea, epigastric discomfort
• Can be reduced by taking with food (at expense of some absorption)

B. Intravenous (IV) Iron (Second-line)

• Oral iron is not tolerated (severe GI side effects)
• Oral iron is ineffective (malabsorption, celiac disease, post-gastrectomy)
• Rapid repletion is needed (perioperative, heart failure, inflammatory bowel disease)
• Ongoing blood loss exceeds oral replenishment capacity

• Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 930

Why IV iron bypasses the gut limitation? Oral iron absorption is limited to ~1-2 mg/day when stores are full (hepcidin rises as iron is replenished, blocking ferroportin). IV iron delivers iron directly to transferrin and the reticuloendothelial system, bypassing the hepcidin-ferroportin regulation.

Caution with iron dextran: Risk of anaphylaxis (highest among IV iron preparations); give a test dose and monitor for 1 hour. Switch to other preparations (iron sucrose, ferric gluconate) which have lower anaphylaxis risk.

C. Blood Transfusion (Reserved for severe/symptomatic cases)

• Only for Hb < 7-8 g/dL with hemodynamic instability, severe symptoms, or cardiac compromise
• Does not address the underlying deficiency - iron supplementation is still required

D. Dietary Advice

• Increase heme iron (red meat, poultry, liver, oysters)
• Avoid tea/coffee with meals (tannins inhibit absorption)
• Add vitamin C-rich foods with iron-containing meals
• Cook in cast-iron pots (small but real effect)

Summary: The "Why" Chain in IDA

Cause (blood loss / low intake / malabsorption / increased need)
       ↓
Storage iron depleted (ferritin ↓, Prussian blue staining absent in marrow)
       ↓
Serum iron ↓ → Liver makes more transferrin → TIBC ↑ → Transferrin saturation ↓
       ↓
Hepcidin ↓ (iron stores low → less HFE signaling to liver)
       ↓
Insufficient iron delivered to erythroid precursors → protoporphyrin accumulates
       ↓
Less hemoglobin synthesized per RBC → smaller, paler cells (microcytic, hypochromic)
       ↓
Iron-containing enzymes in all tissues depleted → koilonychia, glossitis, pica, esophageal webs

Plummer-Vinson Syndrome (Patterson-Brown-Kelly / Sideropenic Dysphagia)

Explained with the "Why" at every step

What Is It?

1. Iron deficiency (microcytic, hypochromic) anemia
2. Atrophic glossitis
3. Postcricoid / upper esophageal webs → dysphagia for solids more than liquids

Why predominantly women? Women of reproductive age have chronically lower iron stores than men (storage iron ~400 mg vs ~1000 mg in men) due to menstrual blood loss and pregnancy demands. This chronic negative iron balance over decades predisposes to the tissue depletion required for this syndrome to develop.

The Central Mechanism: Everything Flows from Iron Depletion

• Cytochromes (mitochondrial electron transport chain - cellular energy production)
• Iron-sulfur cluster enzymes (multiple metabolic pathways)
• Ribonucleotide reductase (DNA synthesis)
• Collagen hydroxylases (connective tissue formation)
• Mucosal enzymes (governing epithelial cell turnover and repair)

Chronic iron deficiency
        ↓
Depletion of iron-containing enzymes in mucosal cells
        ↓
Impaired cellular energy production (cytochromes) + impaired DNA synthesis
        ↓
Mucosal atrophy throughout the upper GI tract
        ↓
Glossitis + esophageal web formation + achlorhydria

Feature 1: Iron Deficiency Anemia (Microcytic, Hypochromic)

• ↓ Serum iron
• ↓ Serum ferritin (< 12 µg/L)
• ↑ TIBC (liver makes more transferrin to scavenge scarce iron)
• ↓ Transferrin saturation (< 15%)
• ↓ Hepcidin (low iron stores → less HFE-mediated signaling to liver → hepcidin falls)

Feature 2: Atrophic Glossitis

• Iron for ribonucleotide reductase (makes deoxyribonucleotides for DNA replication)
• Iron for cytochromes (cellular energy to fuel division)
• Iron for collagen hydroxylases (maintaining mucosal architecture)

Why the tongue specifically? The tongue, along with the rest of the oropharyngeal/esophageal mucosa, has one of the highest epithelial turnover rates in the body. These tissues are therefore the first to show iron-deprivation effects, even before anemia becomes severe.

Feature 3: Esophageal / Postcricoid Webs → Dysphagia for Solids

What are esophageal webs?

Why do webs form in iron deficiency?

1. Iron-dependent enzymes in the upper esophageal mucosa (cytochromes, collagen hydroxylases) become depleted in chronic iron deficiency
2. This leads to mucosal atrophy, submucosal inflammation, and defective repair of the postcricoid region
3. Chronic mucosal damage triggers fibrous healing and web formation - the web is essentially a fold of fibrosed atrophic mucosa
4. Additionally, degeneration of esophageal muscle has been described, possibly contributing to motor dysfunction at the cricopharyngeal level

Why solids more than liquids? Liquids can flow around or through even a narrow, eccentric lumen. Solid food boluses cannot deform enough to squeeze through a luminal diameter of < 12 mm. The dysphagia is therefore predominantly for solids, characteristically intermittent initially and progressive over time.

Why upper/postcricoid region? The postcricoid area is under the greatest mechanical stress during swallowing (high-pressure zone at the cricopharyngeal sphincter) and has a specific mucosal anatomy that makes it vulnerable to iron-depletion injury. - KJ Lee's Essential Otolaryngology

Associated mucosal features

• Angular cheilitis (fissures at mouth corners) - iron-depleted mucosa at the lip commisures
• Koilonychia (spoon nails) - iron-depleted nail matrix enzymes
• Achlorhydria - iron depletion in gastric parietal cell enzymes reduces acid secretion (and in turn, worsens iron absorption - a vicious cycle)
• Hoarseness - pharyngeal/laryngeal mucosal involvement
• Atrophic gastritis, diarrhea - widespread upper GI mucosal atrophy

Investigations

To Demonstrate the Web

Barium swallow showing a proximal esophageal web in Plummer-Vinson syndrome - note the thin transverse band causing luminal narrowing. - Cummings Otolaryngology, p. 1242

• Webs are located so proximally that routine passage of the endoscope through the upper esophageal sphincter (UES) can fracture the web before it is seen - so the endoscope must be introduced under direct visualization
• The web may be missed if the operator is not looking for it
• Endoscopy is also used to perform biopsy to exclude carcinoma and for dilatation if needed

For Iron Deficiency

• CBC: microcytic (↓ MCV), hypochromic (↓ MCH, ↓ MCHC), ↑ RDW
• Serum ferritin (< 12 µg/L), ↓ serum iron, ↑ TIBC, ↓ transferrin saturation
• Peripheral smear: hypochromic microcytes, pencil cells

Cancer Risk: Squamous Cell Carcinoma

• Pharynx (particularly the hypopharynx / postcricoid region)
• Upper esophagus

Other risk factors for esophageal SCC include: alcohol, smoking, achalasia, caustic ingestion, hot beverages, and betel nut chewing - and Plummer-Vinson syndrome sits alongside these. - Fischer's Mastery of Surgery 8th ed.; Cummings Otolaryngology

Why does Plummer-Vinson predispose to SCC? (The key "why")

Important note: The cancer risk justifies regular upper GI endoscopic surveillance, even after the web is treated, because the underlying mucosal vulnerability persists until iron stores are fully normalized.

Treatment: Explained with Why

1. Iron Supplementation (Primary Treatment)

• Restores iron to mucosal enzymes → atrophic mucosa regenerates (glossitis and cheilitis resolve)
• Removes the inflammatory stimulus that drove web formation
• Iron supplementation alone can resolve dysphagia in many patients - the web may soften and retract as the atrophic mucosa heals - Yamada's Textbook of Gastroenterology

2. Web Dilatation (for significant obstruction)

• Bougie dilation (Savary-Gilliard bougies) or balloon dilation at endoscopy
• This mechanically disrupts the web and restores luminal patency
• The procedure is curative in most cases
• Importantly, passage of the endoscope itself sometimes fractures the web inadvertently

3. Regular Upper GI Endoscopic Surveillance

• Indicated because of the elevated SCC risk
• Frequency: typically every 1-3 years depending on risk factors and clinical context
• Allows: early detection of dysplasia or carcinoma at the postcricoid / hypopharyngeal region
• Biopsy of any suspicious area is mandatory

Summary: The Complete "Why" Chain

Chronic iron deficiency
          ↓
↓ Iron-containing enzymes in all high-turnover tissues
          ↓
┌─────────────────────────────────────────────────┐
│ Bone marrow: ↓ Hb synthesis → microcytic anemia │
│ Tongue: mucosal atrophy → glossitis             │
│ Esophagus: mucosal atrophy → web formation      │
│ Nails: matrix enzyme loss → koilonychia         │
│ Stomach: parietal cell enzymes ↓ → achlorhydria │
└─────────────────────────────────────────────────┘
          ↓
Esophageal web (postcricoid) → narrow lumen (< 12 mm)
→ Dysphagia for solids > liquids
          ↓
Chronic mucosal atrophy + impaired DNA repair + food stasis
→ ↑ Risk of postcricoid / hypopharyngeal SCC
          ↓
Treatment: Iron → restore mucosal integrity
           Dilatation → relieve obstruction
           Endoscopy surveillance → detect cancer early

• Sources: Yamada's Textbook of Gastroenterology 7e; Cummings Otolaryngology Head & Neck Surgery; KJ Lee's Essential Otolaryngology; Fischer's Mastery of Surgery 8e; Robbins, Cotran & Kumar Pathologic Basis of Disease