Hematology · PANCE / PANRE

Iron Deficiency Anemia

Microcytic hypochromic anemia from depleted iron stores — most common anemia worldwide.

Also known as: IDA, iron deficiency, microcytic anemia, hypochromic anemia

Overview

Anemia resulting from insufficient body iron to sustain normal erythropoiesis. Defined by reduced hemoglobin with low ferritin (<30 ng/mL in most adults, <15 ng/mL highly specific) and reduced transferrin saturation (<20%).

Epidemiology

Most common cause of anemia globally and in the United States. Highest prevalence in menstruating women, pregnant patients, infants/toddlers, and adults with chronic blood loss. In men and postmenopausal women, GI blood loss must be excluded.

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Question 1HematologyMedium
A 65-year-old man presents with fatigue and exertional dyspnea. Labs show Hgb 8.4 g/dL, MCV 72 fL, ferritin 8 ng/mL, and elevated total iron-binding capacity. He reports no overt bleeding and takes no NSAIDs. Which of the following is the most important underlying cause to exclude?
  • ADietary iron deficiency
  • BBleeding peptic ulcer disease
  • CMalabsorption from celiac disease
  • DOccult gastrointestinal malignancy
Reveal answer & full explanation
Correct answer: D — Occult gastrointestinal malignancy
  • ADietary iron deficiency
  • BBleeding peptic ulcer disease
  • CMalabsorption from celiac disease
  • DOccult gastrointestinal malignancy

Why Occult gastrointestinal malignancy is correct

  • Iron deficiency anemia (low MCV, low ferritin, high TIBC) demands a cause-directed workup.
  • In men and postmenopausal women, occult gastrointestinal blood loss must be investigated with endoscopy/colonoscopy, and GI malignancy is the most important cause to exclude.
  • Low ferritin is the most sensitive indicator of iron deficiency, and a high TIBC supports the diagnosis.

Why the others are wrong

  • A) Dietary iron deficiency — Dietary deficiency is uncommon in adults eating a Western diet.
  • B) Bleeding peptic ulcer disease — H. pylori or idiopathic ulcers can cause occult upper GI blood loss and are evaluated on the same endoscopic workup, but in a 65-year-old man without NSAID use the cause that must not be missed is colorectal or gastric cancer, so malignancy is the most important to exclude.
  • C) Malabsorption from celiac disease — Can cause iron deficiency and should be considered, but is far less likely than occult GI malignancy in an older man and would usually have other malabsorptive features.
Question 2HematologyMedium
A 65-year-old man with no prior GI workup is found to have iron deficiency anemia on routine labs (Hgb 10.2 g/dL, MCV 72 fL, ferritin 8 ng/mL). He is asymptomatic and reports no overt bleeding. Which of the following is the most important cause to exclude?
  • ABleeding peptic ulcer disease
  • BOccult colorectal malignancy
  • CAutoimmune atrophic gastritis
  • DInadequate dietary iron intake
Reveal answer & full explanation
Correct answer: B — Occult colorectal malignancy
  • ABleeding peptic ulcer disease
  • BOccult colorectal malignancy
  • CAutoimmune atrophic gastritis
  • DInadequate dietary iron intake

Why Occult colorectal malignancy is correct

  • Iron deficiency in men and postmenopausal women: GI blood loss is assumed until proven otherwise
  • Colorectal cancer is the most important cause to exclude
  • Colonoscopy is mandatory as the initial evaluation
  • Upper endoscopy is performed if colonoscopy is negative, to evaluate for H. pylori-positive peptic ulcer disease (PUD), gastric cancer, or celiac disease

Why the others are wrong

  • Bleeding peptic ulcer disease — a genuine source of occult upper GI blood loss and part of the bidirectional endoscopic workup, but a missed colorectal cancer carries far greater consequences, so malignancy remains the priority to exclude in a 65-year-old man
  • Autoimmune atrophic gastritis — achlorhydria impairs iron absorption, making it a recognized cause of iron deficiency in older adults that often precedes the B12 deficiency of pernicious anemia, but it is diagnosed on gastric biopsies at upper endoscopy and carries none of the consequences of a missed cancer, so colorectal malignancy remains the priority to exclude
  • Inadequate dietary iron intake — uncommon as the sole cause in an adult man and accepted only after GI blood loss has been excluded

Additional high-yield points

  • In premenopausal women, menorrhagia is the most common cause of iron deficiency
  • Management requires both treating the iron deficiency AND identifying the source
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Risk factors

  • Heavy menstrual bleeding, pregnancy, lactation
  • GI blood loss: peptic ulcer disease, colorectal neoplasm, hookworm, NSAID use, angiodysplasia
  • Malabsorption: celiac disease, atrophic gastritis, H. pylori, post-gastric bypass, PPI use
  • Inadequate intake: strict vegetarian/vegan diet, infants on cow's milk before 1 year
  • Frequent blood donation, hemodialysis
  • Endurance athletes (foot-strike hemolysis, hepcidin elevation)

Pathophysiology

Iron is required for heme synthesis. When demand exceeds supply (loss > absorption), storage iron (ferritin) is mobilized first, then transport iron (transferrin saturation falls), and finally functional iron in erythrocytes. Erythropoiesis becomes iron-restricted, producing small (microcytic), pale (hypochromic) red cells with reduced hemoglobin content.

Clinical presentation

Symptoms

  • Fatigue, dyspnea on exertion, exercise intolerance, lightheadedness
  • Headache, poor concentration, irritability
  • Pica (craving ice/pagophagia, clay, starch) — relatively specific for iron deficiency
  • Restless legs syndrome
  • Hair loss, brittle nails

Signs / physical exam

  • Pallor of conjunctiva, palms, nail beds
  • Tachycardia, systolic flow murmur
  • Koilonychia (spoon nails) — advanced/chronic
  • Angular cheilitis, atrophic glossitis (smooth red tongue)
  • Plummer-Vinson syndrome: dysphagia + esophageal web + IDA (rare, premalignant)

Classic findings

Pica with ice craving plus microcytic anemia and low ferritin is highly suggestive of iron deficiency.

Differential diagnosis

  • Anemia of chronic disease (ACD) — Ferritin normal or elevated (acute phase reactant), low TIBC, low transferrin saturation; iron sequestered by hepcidin
  • Thalassemia trait — Microcytosis disproportionate to mild anemia, normal RDW, Mentzer index <13 (MCV/RBC); hemoglobin electrophoresis abnormal in beta-thal
  • Sideroblastic anemia — Microcytic or dimorphic; ringed sideroblasts on marrow iron stain; elevated ferritin and iron
  • Lead poisoning — Basophilic stippling, occupational/environmental exposure, elevated blood lead level
  • Combined deficiency (B12/folate + iron) — Normocytic MCV with wide RDW; both micro- and macrocytic populations on smear

Diagnostic workup

Diagnostic criteria

Microcytic anemia (Hb low, MCV <80 fL) plus ferritin <30 ng/mL OR transferrin saturation <20% with consistent clinical context.

Labs

  • CBC with peripheral smear — microcytic (MCV <80), hypochromic, anisocytosis (elevated RDW), pencil cells, target cells
  • Iron studies — low ferritin (<30 ng/mL diagnostic in most adults; <100 ng/mL may indicate deficiency in inflammation/CKD), low serum iron, elevated TIBC, transferrin saturation <20%
  • Reticulocyte count — inappropriately low for degree of anemia
  • Soluble transferrin receptor — elevated in IDA, normal in ACD (useful when ferritin uninterpretable)
  • Stool occult blood; consider tissue transglutaminase IgA (celiac screen) in unexplained IDA

Imaging

  • Upper and lower endoscopy in men and postmenopausal women with IDA, and in premenopausal women not responding to iron
  • Capsule endoscopy if EGD/colonoscopy nondiagnostic and bleeding persists

Diagnostic algorithm

ParameterIron DeficiencyAnemia of Chronic DiseaseThalassemia Trait
MCVLowNormal or lowLow (disproportionate)
RDWHighNormalNormal
FerritinLow (<30)Normal or highNormal or high
Serum ironLowLowNormal or high
TIBCHighLowNormal
Transferrin saturationLow (<20%)LowNormal or high
sTfRHighNormalNormal or high
Iron studies pattern across the common microcytic anemias.

Treatment

First-line

  • Identify and correct the underlying cause (most important step)
  • Oral iron — ferrous sulfate 325 mg (65 mg elemental), ferrous gluconate, ferrous fumarate; one tablet every other day improves absorption and tolerability versus daily dosing
  • Take on empty stomach with vitamin C (orange juice) to enhance absorption; avoid concurrent calcium, antacids, PPIs, coffee, tea
  • Continue iron 3-6 months after hemoglobin normalizes to replete stores

Second-line / adjunct

  • IV iron — ferric carboxymaltose, iron sucrose, ferumoxytol, low-molecular-weight iron dextran; indicated for intolerance to oral iron, malabsorption (celiac, IBD, post-bypass), CKD on dialysis, ongoing blood loss exceeding oral absorption, or need for rapid replenishment (late pregnancy)
  • Transfusion reserved for hemodynamic instability, severe symptomatic anemia, or active hemorrhage

Complications

  • High-output heart failure (severe chronic anemia)
  • Impaired neurocognitive development in infants and young children
  • Adverse pregnancy outcomes: preterm birth, low birth weight, postpartum depression
  • Worsened outcomes in HF, CKD, and post-operative recovery
  • Plummer-Vinson syndrome with risk of esophageal squamous cell carcinoma

PANCE pearls

  • Reticulocytosis should be visible within 7-10 days of starting oral iron; hemoglobin rises ~1 g/dL every 2-3 weeks.
  • Failure to respond to oral iron suggests ongoing loss, malabsorption, noncompliance, or wrong diagnosis (think thalassemia, ACD).
  • IV iron does NOT require a test dose for newer formulations (ferric carboxymaltose, ferumoxytol); anaphylaxis risk is much lower than with older high-molecular-weight iron dextran.
  • Ferritin is an acute phase reactant — can be falsely normal in inflammation, infection, malignancy, CKD. Use transferrin saturation and soluble transferrin receptor in these settings.
  • Every-other-day dosing minimizes hepcidin-driven absorption blockade and improves total iron uptake compared to daily dosing.

References

  • ASH 2020 — American Society of Hematology 2020 guidelines for management of iron deficiency anemia
  • AGA 2020 — AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia (Ko et al., Gastroenterology 2020)
  • WHO 2011 — WHO Hemoglobin concentrations for the diagnosis of anemia and assessment of severity
  • Stoffel et al. — Iron absorption from oral iron supplements given on consecutive versus alternate days (Lancet Haematology 2017)

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