Iron Deficiency Anemia

Iron Deficiency Anemia – High‑Yield Study Guide for Medical Students

Definition

Iron deficiency anemia (IDA) is a microcytic, hypochromic anemia caused by insufficient iron to support normal hemoglobin synthesis, resulting in reduced oxygen-carrying capacity of blood.

It is the most common cause of anemia worldwide and represents the late stage of iron deficiency, after depletion of iron stores and transport iron.

Epidemiology

IDA is highly prevalent globally, particularly in populations with increased iron requirements or chronic blood loss.

• Worldwide: Most common nutritional deficiency, especially in low- and middle-income countries.
• High-risk groups:
  • Infants and young children (rapid growth, low dietary iron)
  • Adolescent girls (menarche, growth spurts)
  • Premenopausal women (menstrual blood loss)
  • Pregnant and lactating women (increased requirements)
  • Older adults, especially men and postmenopausal women (occult GI blood loss)
  • Patients with malabsorption (e.g., celiac disease, post-gastrectomy)

Pathophysiology

Iron deficiency anemia develops through a sequence of stages, driven by imbalance between iron supply and demand.

Normal Iron Physiology (High-Yield Basics)

• Body iron content ≈ 3–4 g in adults.
• Distribution:
  • Hemoglobin in RBCs ≈ 65–70%
  • Storage iron (ferritin, hemosiderin) in liver, spleen, marrow ≈ 20–30%
  • Myoglobin and enzymes ≈ 5–10%
  • Transport iron bound to transferrin < 0.2%
• Daily iron loss ≈ 1 mg in men; 1.5–2 mg in women (menstruation).
• Iron absorption occurs mainly in the duodenum and proximal jejunum via divalent metal transporter 1 (DMT1) after reduction of Fe³⁺ to Fe²⁺.
• Hepcidin, a liver-derived hormone, is the key regulator that decreases iron export by degrading ferroportin on enterocytes and macrophages.

Stages of Iron Deficiency

• Stage 1 – Depletion of iron stores:
  • Decreased ferritin (low storage iron)
  • Serum iron and hemoglobin often still normal
• Stage 2 – Iron-deficient erythropoiesis:
  • Low serum iron, increased total iron-binding capacity (TIBC)
  • Transferrin saturation falls
  • Red cell indices may still be normal or show early changes
• Stage 3 – Iron deficiency anemia:
  • Microcytic, hypochromic RBCs
  • Low hemoglobin and hematocrit
  • Overt clinical manifestations of anemia

Mechanisms Leading to Iron Deficiency

• Inadequate intake: poor diet, strict vegan diet without supplementation, infant diet mostly milk-based.
• Decreased absorption:
  • Celiac disease, inflammatory bowel disease involving proximal small bowel
  • Post-gastrectomy, bariatric surgery (e.g., Roux-en-Y gastric bypass)
  • Achlorhydria, chronic PPI use (requires gastric acid for Fe³⁺ → Fe²⁺ conversion)
• Increased loss:
  • Menorrhagia, metrorrhagia
  • Gastrointestinal bleeding (peptic ulcer, malignancy, angiodysplasia, NSAID gastropathy, IBD)
  • Parasitic infection (hookworm, particularly in endemic regions)
  • Repeated phlebotomy or blood donation
• Increased requirements:
  • Pregnancy (fetus + placenta + expanded maternal RBC mass)
  • Lactation
  • Rapid growth in infancy, childhood, adolescence

Clinical Presentation

Symptoms are a combination of general features of anemia and specific features of iron deficiency. On exams, recognize classic patterns and associated causes.

General Symptoms of Anemia

• Fatigue, weakness
• Dyspnea on exertion
• Palpitations, tachycardia
• Headache, dizziness, presyncope
• Reduced exercise tolerance

Signs of Anemia

• Pallor (conjunctival, palmar creases, mucous membranes)
• Tachycardia, flow murmurs, bounding pulses in more severe anemia
• Orthostatic hypotension in significant blood loss

Specific Features of Iron Deficiency

• Pica: craving for non-nutritive substances (ice, clay, starch, paper).
• Pagophagia: specific craving for ice, highly suggestive of iron deficiency.
• Glossitis: smooth, sore tongue.
• Angular cheilitis: fissures at corners of the mouth.
• Koilonychia: spoon-shaped nails (classically described, more chronic/severe cases).
• Hair loss, brittle nails.
• Restless legs syndrome association is common.
• Plummer–Vinson syndrome (rare, but board-relevant): triad of iron deficiency anemia, dysphagia due to esophageal webs, and glossitis; associated with increased risk of squamous cell carcinoma of the esophagus and pharynx.

Diagnosis

Diagnosis integrates clinical context with laboratory evaluation of anemia and iron status. Always search for the underlying cause, especially in adult men and postmenopausal women where IDA is often due to occult blood loss.

Initial Laboratory Evaluation

• Complete blood count (CBC):
  • Low hemoglobin and hematocrit
  • Microcytic anemia: low mean corpuscular volume (MCV < 80 fL)
  • Hypochromic cells: low mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC)
  • Elevated red cell distribution width (RDW) due to anisocytosis
• Peripheral blood smear:
  • Microcytosis, hypochromia
  • Target cells (sometimes)
  • Pencil (elliptical) cells are classic

Iron Studies (Essential for Confirmation)

• Serum ferritin (best initial test of iron stores):
  • Low ferritin confirms iron deficiency in the absence of major inflammation.
  • Remember: ferritin is an acute-phase reactant and may be normal or high in concurrent inflammation.
• Serum iron: decreased.
• Total iron-binding capacity (TIBC): increased.
• Transferrin saturation (serum iron/TIBC × 100): decreased (< 15–20%).

Bone Marrow (Rarely Needed)

• Not routinely required for typical cases.
• If performed, shows absence of stainable iron on Prussian blue stain.

Differential Diagnosis of Microcytic Anemia

If MCV is low, think "TICS" as a common mnemonic:

• Thalassemia
• Iron deficiency
• Chronic disease (anemia of chronic disease/inflammation can be normocytic or microcytic)
• Sideroblastic anemia / lead poisoning

Pattern of iron studies helps distinguish these:

• Iron deficiency anemia: low serum iron, low ferritin, high TIBC, low transferrin saturation.
• Anemia of chronic disease: low serum iron, normal or high ferritin, low TIBC.
• Thalassemia trait: normal or increased iron and ferritin, normal TIBC, normal/high transferrin saturation; more severe microcytosis for degree of anemia; normal RDW.
• Sideroblastic anemia: normal or increased iron and ferritin; ring sideroblasts in marrow.

Workup for Etiology

• History and physical focused on diet, menstruation, pregnancy, GI symptoms, medications (NSAIDs, anticoagulants), prior surgeries (gastrectomy/bariatric), and blood donation.
• Premenopausal women:
  • Assess menstrual history (menorrhagia, intermenstrual bleeding)
  • Consider gynecologic evaluation if heavy or irregular menses
• Men and postmenopausal women:
  • High suspicion for gastrointestinal blood loss
  • Usually need endoscopic evaluation (upper endoscopy and colonoscopy) to exclude malignancy, ulcers, angiodysplasia, IBD, etc.
• Consider celiac serologies if suspicion for malabsorption or concurrent symptoms.

Management

Treatment of iron deficiency anemia has two pillars: correcting iron deficiency and identifying and addressing the underlying cause.

General Principles

• Do not treat empirically without a plan to evaluate cause, particularly in adult men and postmenopausal women.
• Oral iron is first line in most stable patients.
• Intravenous (IV) iron is used when oral iron is ineffective, not tolerated, or contraindicated, or when rapid repletion is needed.
• Transfusion is reserved for severe or symptomatic anemia.

Oral Iron Therapy

• Common preparations (doses expressed as elemental iron):
  • Ferrous sulfate 325 mg tablet ≈ 65 mg elemental iron
  • Ferrous gluconate 325 mg ≈ 35 mg elemental iron
  • Ferrous fumarate 325 mg ≈ 106 mg elemental iron
• Dosing strategy (adults):
  • Traditional: 100–200 mg elemental iron/day divided in 2–3 doses.
  • Recent data support once-daily or alternate-day dosing to improve absorption and tolerance (due to lower hepcidin induction).
• Administration tips:
  • Best absorbed on an empty stomach; however, may be taken with food if GI side effects are problematic.
  • Vitamin C (ascorbic acid) or orange juice can enhance absorption.
  • Avoid co-administration with calcium, antacids, PPIs, tea, coffee, or high-fiber foods near dosing time, as they reduce absorption.
• Side effects:
  • GI upset: nausea, abdominal pain, constipation or diarrhea
  • Dark stools (benign, but important counseling point)
  • Adherence often limited by GI symptoms; changing formulation or dose frequency may help.
• Monitoring response:
  • Reticulocyte count rises in 3–7 days.
  • Hemoglobin increases by ≈ 1–2 g/dL every 2–3 weeks in adequately treated and adherent patients.
  • Continue oral iron for 3 months after normalization of hemoglobin to replenish iron stores.

Intravenous Iron Therapy

• Indications:
  • Intolerance or poor adherence to oral iron
  • Malabsorption (e.g., celiac disease, after bariatric surgery)
  • Ongoing blood loss exceeding capacity of oral replacement
  • Need for rapid repletion (late pregnancy, severe anemia pre-surgery)
• Preparations (exam-level knowledge): iron sucrose, ferric carboxymaltose, iron dextran, ferric gluconate, etc.
• Advantages: Bypasses GI tract; allows full repletion in a small number of infusions.
• Risks:
  • Infusion reactions; anaphylaxis risk particularly with older high-molecular-weight iron dextran (less with newer preparations).
  • Hypotension, flushing, arthralgias, myalgias.

Red Blood Cell Transfusion

• Used for severe, symptomatic anemia (acute blood loss, hemodynamic compromise, or very low hemoglobin with end-organ ischemia).
• Transfusion temporarily corrects anemia but does not fix iron deficiency; patients usually still require iron replenishment.

Addressing Underlying Cause

• Treat menstrual blood loss (hormonal therapy, fibroid management, etc.).
• Identify and treat GI sources (e.g., PPI and eradication therapy for H. pylori, surgery or oncology referral for malignancy, treating angiodysplasia, IBD therapy).
• Nutritional counseling for inadequate iron intake.
• Manage malabsorptive conditions (e.g., gluten-free diet for celiac disease).

Key Clinical Pearls and Exam Tips

• Most common cause of anemia worldwide is iron deficiency anemia.
• In adult men and postmenopausal women, IDA is colon cancer until proven otherwise – always think occult GI blood loss and malignancy.
• First laboratory abnormality in iron deficiency is decreased ferritin, followed by decreased serum iron and increased TIBC, then anemia.
• Classic iron studies in IDA: ↓ ferritin, ↓ serum iron, ↑ TIBC, ↓ transferrin saturation.
• Peripheral smear: microcytic, hypochromic RBCs with pencil cells.
• Pica (especially pagophagia) and restless legs are strongly associated with iron deficiency.
• IDA vs thalassemia: IDA has high RDW, low RBC count; thalassemia trait often has normal RDW and relatively high RBC count despite low MCV.
• Plummer–Vinson syndrome: iron deficiency anemia + dysphagia + esophageal webs and increased risk of upper GI squamous cell carcinoma.
• Ferritin is an acute-phase reactant: normal or high ferritin does not always exclude IDA if there is significant inflammation; in such cases, look at transferrin saturation and clinical picture.
• Oral iron should be continued for ~3 months after normalization of hemoglobin to fully replenish iron stores.
• Alternate-day oral iron dosing may improve absorption and reduce GI side effects by avoiding hepcidin spikes.

Quick Summary Table (For Last-Minute Review)

Exam-Oriented Clinical Vignettes (Patterns to Recognize)

• Young woman with heavy menstrual bleeding → fatigue, low MCV, low ferritin → treat with oral iron and manage menorrhagia.
• Older man with fatigue and microcytic anemia → think occult GI blood loss → colonoscopy to exclude colorectal cancer.
• Post-gastrectomy patient with anemia and low ferritin → iron deficiency due to reduced absorption → consider IV iron if oral ineffective.
• Child with pica and milk-heavy diet → iron deficiency anemia due to low dietary iron → diet modification and oral iron.