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Anemia , classifications and iron deficiency anemia

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"iron deficiency anemia" AND diagnosis

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Anemia: Classifications and Iron Deficiency Anemia

Definition

Anemia is defined as a reduction in blood counts (hemoglobin, hematocrit, or red cell number) below the normal range for a given population. It is not a diagnosis in itself but a manifestation of an underlying process.
  • Harrison's Principles of Internal Medicine 22E, p. 492

Classifications of Anemia

There are two major ways to classify anemia: by red cell size (morphologic/MCV-based) and by mechanism (pathophysiologic).

1. Morphologic Classification (by MCV)

Pioneered by hematologist Max Wintrobe, this is the most clinically practical approach because MCV guides the diagnostic workup.
CategoryMCVCauses
Microcytic< 80 fLIron deficiency, thalassemia, anemia of chronic disease/inflammation, sideroblastic anemia
Normocytic80-100 fLAplastic anemia, renal disease, endocrinopathies, myeloma, marrow invasion, pure red cell aplasia
Macrocytic> 100 fLOval macrocytes: B12 deficiency, folate deficiency, chemotherapy, myelodysplasia; Round macrocytes: alcohol use, hypothyroidism, liver disease, reticulocytosis, dysproteinemia
Note: Anemia of chronic disease typically shows normocytic cells, though it can be microcytic in severe or prolonged cases.
  • Harrison's Principles of Internal Medicine 22E, p. 492

2. Mechanistic Classification (by Pathophysiology)

The reticulocyte count is the key first step: elevated reticulocytes point to increased destruction/loss; low reticulocytes point to underproduction.

A. Blood Loss

  • Acute: trauma
  • Chronic: GI lesions (peptic ulcer, colorectal cancer), gynecologic causes

B. Increased Red Cell Destruction (Hemolysis)

Inherited (intrinsic) causes:
  • Red cell membrane disorders: hereditary spherocytosis, hereditary elliptocytosis
  • Enzyme deficiencies: G6PD deficiency (HMP shunt), pyruvate kinase deficiency (glycolysis)
  • Hemoglobin abnormalities: thalassemia syndromes (deficient globin synthesis), sickle cell disease, unstable hemoglobins
Acquired causes:
  • Paroxysmal nocturnal hemoglobinuria (PNH) - phosphatidylinositol-linked glycoprotein deficiency
  • Antibody-mediated: autoimmune hemolytic anemia, hemolytic disease of the newborn, transfusion reactions, drug-induced
  • Microangiopathic hemolytic anemia (MAHA): HUS, DIC, TTP
  • Cardiac traumatic hemolysis: defective valves
  • Infections: malaria, babesiosis
  • Repetitive physical trauma (march hemoglobinuria)

C. Decreased Red Cell Production (Underproduction)

  • Nutritional deficiencies: iron deficiency (impairs heme synthesis), B12/folate deficiency (impairs DNA synthesis), copper, Vitamin C
  • Erythropoietin deficiency: renal disease, anemia of inflammation, anemia of aging
  • Stem cell/progenitor failure: aplastic anemia, pure red cell aplasia, Fanconi anemia
  • Marrow replacement: metastatic neoplasms, granulomatous disease, infections
  • Primary hematopoietic neoplasms: leukemia, myelodysplastic syndromes
  • Robbins, Cotran & Kumar - Pathologic Basis of Disease, Table 14.1

Iron Deficiency Anemia (IDA)

Iron deficiency is the most common nutritional disorder in the world and the most common cause of anemia globally.

At-Risk Populations

  • Infants and toddlers
  • Adolescent girls
  • Women of childbearing age (due to menstruation)
  • Pregnant women
  • People in low-resource countries (poor diet + parasite burden)

Iron Metabolism (Normal)

Iron Distribution in Healthy Adults:
PoolMales (mg)Females (mg)
Total34502450
Hemoglobin21001750
Myoglobin300250
Enzymes5050
Storage (ferritin/hemosiderin)1000400
Iron metabolism cycle - from intestinal absorption through plasma transferrin to bone marrow erythroid precursors and circulating red cells, with daily losses of 1-2 mg via skin, gut, and endometrium
Key points of iron metabolism:
  • No regulated excretion pathway - daily losses limited to 1-2 mg (shed epithelial cells)
  • Dietary iron: 10-20 mg/day in the US diet; ~20% of heme iron is absorbed vs. only 1-2% of nonheme iron
  • Iron is transported in plasma bound to transferrin (normally ~1/3 saturated)
  • Storage forms: ferritin (water-soluble, found in hepatocytes/macrophages) and hemosiderin (aggregated ferritin in lysosomes; stains Prussian blue)
  • Regulation: Hepcidin (liver peptide) binds and degrades ferroportin, blocking iron transfer from enterocytes and macrophages into plasma. High iron body stores = high hepcidin = less absorption; low stores = low hepcidin = more absorption

Etiology of IDA

Iron deficiency results from one or more of these four mechanisms:
  1. Dietary lack - more common in low-resource countries where diet is predominantly non-heme iron (poorly absorbed). Rare in developed nations.
  2. Impaired absorption - celiac disease, post-gastrectomy, achlorhydria, drugs (antacids, PPIs), TMPRSS6 mutations (rare)
  3. Increased requirement - pregnancy (fetal demand + blood volume expansion), infancy/adolescence (rapid growth), lactation
  4. Chronic blood loss - the most important cause in adults in high-resource countries
    • GI blood loss: peptic ulcers, esophageal varices, colorectal cancer, angiodysplasia, hookworm
    • Gynecologic: menorrhagia, fibroids
    • Repeated phlebotomy or hemodialysis
    • Pulmonary hemosiderosis
Important: In adult men and postmenopausal women, IDA should always trigger a search for a GI source of bleeding, as occult colorectal cancer is a significant concern.
  • Robbins, Cotran & Kumar - Pathologic Basis of Disease, p. 614

Stages of Iron Deficiency

StageFeatures
Pre-latent (Iron depletion)Depleted bone marrow stores; serum ferritin falls; no anemia yet
Latent (Iron-deficient erythropoiesis)Serum iron falls, TIBC rises, transferrin saturation falls; no anemia
Iron deficiency anemiaHemoglobin falls; microcytic hypochromic anemia develops

Pathologic Blood Film

IDA peripheral blood smear showing hypochromic microcytic red cells with a narrow rim of peripheral hemoglobin. A normally hemoglobinized cell (from recent transfusion) is visible for contrast.
Fig: Iron deficiency anemia - peripheral blood smear showing hypochromic microcytic red cells containing a narrow rim of peripheral hemoglobin. (Robbins, Cotran & Kumar - Pathologic Basis of Disease)

Clinical Features

Anemia-related (general):
  • Fatigue, pallor, dyspnea on exertion, palpitations, weakness, headache
IDA-specific (from depletion of iron-containing enzymes throughout the body):
  • Koilonychia (spoon-shaped nails)
  • Angular cheilitis (cracking at corners of mouth)
  • Glossitis (atrophy of tongue papillae, sore tongue)
  • Pica - craving for non-foodstuffs (clay = geophagia; ice = pagophagia; starch = amylophagia)
  • Plummer-Vinson syndrome (rare): triad of microcytic hypochromic anemia + atrophic glossitis + esophageal webs
  • Alopecia, gastric mucosal atrophy, intestinal malabsorption
  • Restless legs syndrome - iron depletion from the CNS

Laboratory Diagnosis

TestFinding in IDA
Hemoglobin / HematocritLow
MCVLow (< 80 fL)
MCH / MCHCLow (hypochromia)
Serum ironLow
TIBC (Total Iron-Binding Capacity)High (reflects elevated transferrin)
Transferrin saturation< 15% (normally ~20-45%)
Serum ferritinLow (< 12 µg/L)
HepcidinLow (suppressed by iron depletion)
ReticulocytesLow (before treatment)
Peripheral smearMicrocytic, hypochromic RBCs; poikilocytosis (pencil cells, target cells)

IDA vs. Anemia of Chronic Inflammation (ACI) - Key Distinction

ParameterIDAACI
Serum ironLowLow
TIBCHighLow
Transferrin saturationLowLow
Serum ferritinLowHigh/Normal
Storage iron (bone marrow)AbsentIncreased
HepcidinLowHigh (IL-6 driven)
In ACI, inflammatory mediators (especially IL-6) stimulate hepcidin production, locking iron inside macrophages and preventing its use by erythroid precursors - "iron in the midst of plenty."

Treatment

Oral iron supplementation is first-line:
  • Ferrous sulfate 325 mg three times daily (contains ~65 mg elemental iron per tablet)
  • Take on an empty stomach; Vitamin C enhances absorption
  • Response: reticulocyte count rises in 5-7 days, followed by steady Hb rise
  • Full correction of Hb takes 6-8 weeks; iron stores take 3-6 months to replenish
  • Common side effects: constipation, nausea, dark stools
IV iron (ferric carboxymaltose, ferric gluconate, iron sucrose, low-molecular-weight iron dextran):
  • Used when oral iron is not tolerated, not absorbed (malabsorption), or blood loss exceeds what oral supplementation can replace
  • Preferred in inflammatory bowel disease, post-bariatric surgery, CKD, heart failure, pregnancy with severe IDA
Treat the underlying cause - this is as important as supplementation. Without correcting the source of blood loss or nutritional inadequacy, recurrence is inevitable.
Sources: Harrison's Principles of Internal Medicine 22E; Robbins, Cotran & Kumar - Pathologic Basis of Disease; Goldman-Cecil Medicine; Robbins & Kumar Basic Pathology
Recent evidence: A 2026 systematic review and meta-analysis (PMID: 41241142) on pediatric IDA treatment confirms oral iron is effective first-line therapy, with IV iron as a safe alternative for refractory cases.
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